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Twenty-four-year-old Kara Zor-El, cousin of Superman, who was taken in by the Danvers family when she was 12 after being sent away from Krypton, must learn to embrace her powers after previously hiding them.
A new Fort Rozz prisoner, Hellgrammite, commits a series of robberies of chemical manufacturing plants. While the DEO goes after him, Supergirl discovers that fame is fickle when the public turns against her after a series of mishaps.
Supergirl faces her first non-alien nemesis when one of her cousin's enemies--the nuclear-powered Reactron--comes looking to kill her. Meanwhile, Cat runs a derogatory exposé on Supergirl after interviewing the superhero.
Kara has her hands full dealing with her foster mother Eliza's visit as well as a new super-villain, Livewire, who is out for revenge against Cat.
Kara finds herself juggling her personal and public lives when she offers to take care of Cat's son Carter, deal with James' relationship with Lucy, and try to stop a bomber who is targeting Maxtech properties.
While Kara deals with personal pressures as both office assistant and superhero, General Sam Lane arrives in National City to field-test his new anti-insurgent android, Red Tornado... and to tell James that he's not good enough for his daughter Lucy. Meanwhile, Alex and Kara ask Winn to hack the DEO mainframe to find out how Jeremiah died, and Cat deals with her domineering mother.
Kara is still without her powers when an earthquake rocks National City. Now she and her friends must rise to the occasion. Meanwhile, the DEO's attempts to restrain an escaped prisoner are threatened by Alex's mistrust of Hank after she learns of his role in Jeremiah's death.
Astra calls Supergirl out to fight, but soon loses. However, Hank and Alex suspect that the Kryptonian general lost too easily. Meanwhile, an email hack threatens Cat's position as CEO of CatCo, and Kara learns that someone is trying to force her boss out of the company.
Supergirl tries to convince her aunt to help them recover Hank from the Kryptonians and is forced to rely on blind faith. Meanwhile, Max continues his campaign to bring down Supergirl, and Kara tries to convince Cat that she and Supergirl are not one and the same.
The Toyman--Winn's father--breaks out of prison and begins a new criminal rampage on a quest to be reunited with his son. Meanwhile, Lucy accepts a job at CatCo, much to Jimmy's discomfort.
Kara must help Hank face his painful past when a White Martian, a member of the alien race that wiped out his people, kidnaps Senator Miranda Crane, an anti-alien politician. Also, Cat's estranged son, Adam, arrives in National City.
Max creates a reverse image of Supergirl using her DNA, and sets it to fight the Woman of Steel. Meanwhile, James and Winn share a drink, and Max reveals to Alex how much he knows about her connection to Supergirl.
Supergirl is ensnared by an alien plant that forces her into her deepest desire, and her friends and sister must free her before it's too late. Meanwhile, the Kryptonians launch their plan to bring humanity to its knees and save Earth.
An armored alien with advanced tech is hunting down the Fort Rozz prisoners... and executing them. While Supergirl tries to find him, James questions whether the DEO has the right to lock up Max without charges or a trial. Meanwhile, Kara tries to deal with Cat's new assistant at work, who is intent on upstaging Kara.
A new enemy emerges to threaten Supergirl and National City... and has a connection to Krypton. Meanwhile, Lucy demands the truth from James, and Kara continues refusing to work with Hank, unaware that Alex is the one who killed Astra.
After defending Supergirl to the public, Cat is forced to issue a public warning after exposure to Red Kryptonite turns Supergirl into a power-mad villain.
A captive Hank tells the U.S government how he came to lead the DEO, but receives a less than sympathetic ear. Meanwhile, Kara reveals her identity to someone close to the investigation, and Siobhan plans revenge Kara for getting her fired from CatCo.
Supergirl finds herself in a super team-up when a new superhero, The Flash, accidentally crosses dimensions and finds himself in Kara's universe. Together they have to battle Livewire and a new villainess, Silver Banshee.
Kara must find a way to free her friends when Non and Indigo use mind control to turn National City's citizens into their own army.
To stop Non from wiping out Earth's population, Supergirl has no choice but to sacrifice her life. Before she does so, Kara says goodbye as best she can to her friends without telling them the truth and inciting a panic.
After a seemingly Kryptonian pod crashes in National City, Superman comes to visit his cousin. While the two of them try to determine if Lena Luthor--Lex's sister--is up to no good, Kara wrestles with her personal life.
Cadmus creates a second Metallo and declares war on any aliens on Earth. Meanwhile, Kara finds her new boss less than sympathetic, and Cat gives her surprising news.
Supergirl and the DEO are called on to protect the President when she comes to National City to sign her Alien Amnesty Act. However, a hostile alien threatens to kill the President and anyone who gets in its way. Meanwhile, Alex meets Maggie Sawyer, a detective with the NCPD's science division, and Snapper challenges James' authority.
While Hank tries to bond with Megan, Supergirl and Alex discover that a woman named Roulette is running an underground fight club using aliens as gladiators. Meanwhile, Mon-El convinces Winn to take him out for a night on the town.
Cadmus provides a gang of crooks with alien weaponry in an attempt to spread fear and panic among the populace. Meanwhile, Kara tries to mentor Mon-El with minimal success, and James decides that he wants to be a superhero.
Supergirl battles a scientist who has been possessed by an alien parasite, giving the ability to drain the lifeforce from anyone he touches. Meanwhile, Alex comes out to Kara, and the Guardian makes his first public appearance.
While Cadmus captures Supegirl and Mon-El, Guardian and Winn go after a murderous vigilante that is letting Guardian take the blame for his murders. Meanwhile, Alex and Maggie have issues.
When the Danvers celebrate Thanksgiving, Alex tries to find the right time to tell her mother Eliza that she's gay. Meanwhile, Lena is forced to choose when Supergirl tells her that Lillian plans to unleash a virus that will wipe out every alien in the city.
Crossover among four CW shows: Supergirl "Medusa"; The Flash "Invasion!"; Arrow ‘Invasion!"; DC's Legends of Tomorrow "Invasion!"
When a girl disappears, Kara discovers a pattern of missing people and goes looking with Mon-El... and they both end up on an alien planet under a red sun which renders them powerless. Meanwhile, Winn has a brush with death, and Alex and Maggie have their first disagreement.
Livewire escapes prison, but the DEO soon realizes that she wasn't a willing escapee. Meanwhile, Megan collapses and Hank refuses to mind-meld with her to find out what is wrong with her, and James considers telling Kara that he's Guardian.
M'gann's White Martian mate Armek comes to Earth to bring her back to face justice for her "treachery' When she takes refuge in the DEO, Armek infiltrates the building and uses his shapeshifting powers to spread confusion.
Metallo breaks Lillian out of jail and the evidence shows that Lena was responsible. Kara is the only one who believes that Lena is innocent, and sets out to prove it.
It's Valentine's Day, and Kara finds herself dealing with the amorous advances of Mxyzptlk, a fifth-dimensional being with unlimited magical powers. Meanwhile, Alex discovers that Maggie hates Valentine's Day, while an alien woman hits on Winn.
The DEO manages to rescue Jeremiah from Cadmus, but Mon-El's suspicions soon drive a wedge between him and the Danvers sisters. Meanwhile, Cadmus continues with its master plan to cleanse the planet of alien influence.
Alex refuses to obey Hank's orders to stand down and sets out to find Cadmus and protect Jeremiah. Meanwhile, Kara takes drastic steps when Snapper refuses to publish her story intended to protect the remaining aliens on Earth from Cadmus.
Mon-El's parents arrive to bring home and help restore Daxam to its former glory... and Supergirl realizes that Mon-El has been lying to her. Meanwhile, Winn discovers that Lyra has set him up when he's the prime suspect in a museum robbery. The Music Meister puts Supergirl into a coma and the story line concludes in The Flash: "Duet", Season 3, Episode 17.
Someone hires bounty hunters to kill Supergirl, and Mon-El believes that his parents are responsible. Meanwhile, Maggie and Alex run into Maggie's old girlfriend, and President Marsdin gives express orders to Hank not to attack the Daxamites.
Lena's ex, Jack Spheer, arrives in National City to roll out a new nanite medical procedure. However, Kara soon realizes that something more is going on when one of the human test subjects die under mysterious circumstances. Meanwhile, Lyra comes between Winn and James in their crimefighting efforts.
A man abducts Alex and threatens to kill her unless Kara helps a supermax prisoner escape... and the abductor knows that Kara is Supergirl. Meanwhile, Rhea approaches Lena with an offer.
Alien refugees, the Phorians, trigger telekinetic quakes every time that Lena and Rhea activate the portal. While James tries to get through to one alien boy who knows where the others are, the DEO tries to find the portal before it's too late for National City.
Alex takes over as Acting Director of the DEO as the Daxamites take over National City, open fire on Air Force One, and recruit a familiar face to their side. Meanwhile, Cat Grant returns to National City to inspire Supergirl and the populace.
Lillian comes up with the ultimate weapon to drive the Daxamites off of Earth, but Supergirl is reluctant to make the sacrifice necessary. Instead, she challenges Rhea to a ritual trial by combat to save National City and Earth. Superman returns. Cat Grant offers Supergirl some sage advice.
After losing Mon-El, Kara decides to give up her human life and dedicate herself full-time to being Supergirl. Meanwhile, a new menace threatens National City, and real estate mogul Morgan Edge makes a bid to buy up CatCo. Also, Alex confesses a secret to Maggie, a citizen of National City has a mysterious connection to Kara, and Lena makes a bold move.
Supergirl faces Psi, a thief who can psychically induce her victims' worst fears. Meanwhile, James deals with having a new boss at CatCo, and Alex and Maggie continue making plans for their wedding.
Supergirl goes with Hank to Mars in response to M'gann's telepathic request for help. Meanwhile, Maggie invites her estranged father Oscar to her and Alex's wedding shower that's sponsored by Eliza.
Kara learns of a cult-like organization of people that she's rescued... who consider her a god. Meanwhile, Sam has difficulty balancing her career with her personal life.
Morgan accuses Lena of poisoning the children of National City with the lead bomb she used to drive off the Daxamites. Kara and Sam work to clear their friend's name. Meanwhile, Maggie and Alex break up.
Kara takes Alex home to Midvale after Alex and Maggie break up. While Alex deals with the end of her relationship, she and Kara remember the first time that they bonded as sisters while solving the murder of a fellow high school student.
The DEO rescues Mon-El from a spaceship buried in 12,000 years of rock, but Mon-El remains strangely silent about how he got there. Meanwhile, Hank takes M'yrnn to the park, and Sam goes to her mother Patricia for answers about her birth.
Rather than wallow in self-pity, Kara and Alex go to Barry Allen and Iris West's wedding... only to find the ceremony interrupted by Nazi soldiers and villains from Earth-X including a mysteriously strong superpowered female warrior.
Supergirl learns that a mysterious Kryptonian symbol suddenly appearing around the city heralds the appearance of the World Killer, Reign. She's a Kryptonian whose powers exceed Supergirl's... and who is determined to bring judgment to a sinful world. The tension between Lena and Morgan Edge continues to build.
Mon-El and Imra decide whether to help the DEO battle Reign. Meanwhile, another Legionnaire attempts to help Kara emerge from the coma that Reign put her into after their battle.
Supergirl and Saturn Girl are forced to recruit two female metas to find a prisoner on Fort Rozz, which is orbiting a sun that emits radiation fatal to males. Meanwhile, Alex babysits Ruby while Sam goes on a work trip.
Morgan believes that a recent attempt on his life was made by Lena. When Lena is poisoned, Kara steps in to find out who is responsible for the escalation in hosility. Meanwhile, Sam turns to Alex for help determining the cause of her blackouts.
The DEO easily captures Julia Freeman, the second Worldkiller Purity's body. While Supergirl and Alex try to get through to her, Mon-El asks Hank for his help repairing the Legion Cruiser.
After Winslow dies, his wife Mary comes to National City to attempt to reunite with Winn. However, a new murderous toymaker threatens Winn and Mary, Meanwhile, M'yrnn asks Alex to keep a secret from Hank, and Mon-El tries to find the right time to tell Supergirl something important about one of the Worldkillers.
M'yrnn tries to redirect his mental processes and ends up infecting the DEO with a telepathic rage virus. Meanwhile, Lena tries to convince Sam that the latter transforms into Reign during her blackouts.
The third Worldkiller, Pestilence, begins striking down the citizens of National City.... including Winn and Alex. Supergirl and Imra disagree on how to deal with Pestilence, and Lena continues trying to find a cure for Sam.
Supergirl discovers that she has a mental link to Sam and Julia, and takes Lena and Alex with her to rescue them. Meanwhile, James faces a tough decision when he must decide whether to investigate Lena or not after she kept Reign's existence a secret.
Lena provides Alex with a safehouse to protect Ruby from Reign, who is looking to severe the last ties of humanity that Sam has with her family. Meanwhile, Supergirl discovers that Lena has been manufacturing Kryptonite, and the Legionnaires depart for the future.
Followers of Coville plan to use his journal to create a new Worldkiller. Meanwhile, Supergirl tries to repair the rift between her and Lena, and James is forced to consider whether to out himself or not.
Supergirl and Mon-El find a remnant of Krypton drifting deep in space. Meanwhile, Alex faces a killer from her past, and Winn ends up babysitting Ruby.
Kara and Mon-El return to Argo City, but not all is as it seems. Meanwhile, in Supergirl's absence, Guardian and the DEO deal with a dangerous gunman wielding DEO weaponry.
Supergirl and Mon-El try to get to Earth to stop the Daughters of Juru from resurrecting Reign and triggering Earth's destruction. Meanwhile, Hank participates in The Reach with his father, and Ruby demands the truth from Sam.
The heroes must come up with a way to defeat Reign without killing her. Afterward, Winn and Alex get job offers, Mon-El and Hank make decisions about their personal lives, and James has a news story for the world.
With Superman off-world, Supergirl becomes a worldwide beacon of hope. Meanwhile, Lena takes secret measures to keep James out of prison, while Kara welcomes a new report to CatCo and Alex and Brainiac-5 get off to a rocky start after the latter takes Winn's position at the DEO.
The U.S. people are shaken by the revelation that the President is an alien. As Supergirl tries to quell the unrest, Nia tells James that he should write an editorial supporting aliens. Meanwhile, Mercy launches an attack on L-Corp to shut down the image inducers and reveal the aliens for who they really are.
While the DEO try to save Supergirl's life, the events leading up to the creation of Agent Liberty are shown.
To heal Supergirl, Alex assigns Brainiac-5 and Lena to find a way to remove the Kryptonite from Earth's atmosphere. Meanwhile, Mercy and Otis abduct aliens from a DEO facility and use them to attack children and spread fear, and Hank meets an ally in his fight.
When Jensen--the new Parasite--attacks aliens, Supergirl is forced to take to the sidelines rather than give him further power. As a result, Kara writes an article on an alien healer who makes him a target. Meanwhile, Alex learns some surprising things about her new superior, and James comes to a realization about the Children of Liberty and their anti-alien agenda.
As the Thanksgiving holiday approaches, the Children of Liberty prepare a new initiative to wipe out the aliens among them. James and Lena have their first major argument, and Nia displays narcolepsy but refuses help.
Hank assures Supergirl that Manchester is a trustworthy ally. Meanwhile, James meets with Agent Liberty and has to choose between betraying his reputation or committing an act of terrorism for the Children of Liberty.
Manchester learns Agent Liberty's secret identity and goes to obtain vengeance for Fiona's death. Nia has a prophetic dream, and Kara and Brainiac-5 help her to avoid the future that she has foreseen.
Deegan "thinks big" and rewrites the reality of Earth-1 so that he's the only superhero... and a familiar face. While Barry and Oliver try to contact Superman on Earth-38, Kara tries to get through to her foster sister Alex... who no longer remembers who Kara is.
Supergirl finds a ship full of dead SEAL soldiers, and discovers that it's connected to Haley and the US government. Brainiac-5 sets up a meeting—at a romantic restaurant—with Nia to discuss her future as a possible superhero, and Lena tells James what she's been working on.
Kara travels with Nia to the latter's hometown and discovers that Nia is inheriting the Dreamer power from her mother... which has skipped Nia's sister Maeve. In National City, an outbreak of a new drug rage starts and Alex investigates while asking J'onn to determine if she's having memory problems.
Kara continues to deal with the fallout from Alex's mindwipe, and a new villain enters National City: Menagerie, a human jewel thief merged with an alien symbiote. Nia invites Brainiac-5 to her Valentine's Day party, and Ben reaches out to his wife and son.
Manchester assembles a team of Supergirl's old and new opponents to break him out of prison and form The Elite. Meanwhile, President Baker reaches out to Ben and soon asks him for more than photo ops.
Ben proposes to end the Alien Amnesty Act and holds a rally. Alien protesters hold a peaceful march, but Manchester plans to disrupt the event using stolen Kryptonian technology... and reveal J'onn's true feelings. James goes to the rally to cover events as a photographer.
James undergoes surgery to replace his shattered spine, and Lena has no choice but to work with her brother Lex to perfect the Harun-El serum to cure James before he dies. J'onn and Kara track down Manchester, who has recovered the Staff of H'ronmeer and attempts to turn J'onn from the path of peace.
Lex spends three years plotting his next scheme, working with the Kaznian government to train the Supergirl clone to further their ambitions against America so that he can step in and stop them, becoming a hero to the world and its savior.
J'onn has a meeting with his deceased father, while Supergirl, Alex, and Lena join forces to track down Eve and locate Lex.
Supergirl and Lena go to Stryker's Island to check out Lex's cell, and find a clue to his schemes. Supergirl is declared a criminal and is forced to question whether she does more harm or good, while James deals with the fallout from being injected with the serum.
Kara tries to convince an Amertek insider to provide her with information proving a connection to Lex. Dreamer agrees to a TV interview, and Brainiac-5 helps James explore the cause of his PTSD.
Kara and Lena track Lex to Kaznia, and find Eve but no Lex. Ben abandons his son to go after his wife's killer, which pits him against Brainiac-5, Dreamer, and the newly superpowered James. Alex and Kelly travel to meet with a woman giving birth to a child who could become Alex's.
Supergirl and Alex go after Red Daughter, while Lena and James hunt down Ben. Brainiac-5, J'onn, and Dreamer attempt to rescue the alien prisoners, but two of them are captured and one of them is "rebooted".
Lex's plan reaches fruition: Red Daughter has defeated Supergirl, Lex has defeated the Kaznians and then Red Daughter. Now only one thing can stop him: the power of the Fourth Estate.
Kara prepares to accept a Pulitzer for her writing, and comes to a decision about sharing her secret identity with Lena. A new villainess and former foe emerges from the Phantom Zone to fight John, and Lena sells CatCo to an associate who has big changes in store for the organization.
John tells the others about Malefic's attack on him, and discovers that some of his memories have been erased. While Kelly helps John determine the extent of the psychic attack, Supergirl, Alex, and Querl search for Malefic. Meanwhile, Andrea demands more from Kara at work, and Lena questions Eve's loyalties.
Kara meets with Lena for the first time since she admitted her secret identity to her. J'onn recruits Nia to help him dwell further into his memories, and Nia deals with her relationship with Querl. An old friend visits Kelly and asks for help with his memories, but he isn't what he seems.
Kara continues to investigate what William is up to, while Malefic launches an attack on John's friends through Alex. James and Kelly return to their hometown and discover corruption... and no one willing to stand up to it.
On the eve of the worldwide launch of Andrea Rojas's VR contact lenses, Kara and William team up on an investigation that exposes a terrorist plot. Kelly and Alex celebrate an anniversary, but Alex's safety is in jeopardy.
While a new villain is under arrest at the DEO, Supergirl uses him to try and understand who is responsible for the recent attacks. Meanwhile, Andrea and Lena think back on their tumultuous past.
Leviathan's leader comes after Lena to get the medallion, and Lena convinces Supergirl to take her to the Fortress to find a weapon capable of stopping him. Kelly makes a confession to Alex, and John reaches out to his brother.
Alex is torn between destroying Lena before she can unleash Myriad, or using Malefic to stop the Luthor's mind-control plan. Meanwhile, Khan prepares to wipe humanity from the planet.
Harbinger gathers the greatest heroes of several worlds to battle the Anti-Monitor, his shadow demons, and the anti-matter wave that is sweeping across the multi-verse. While Lois, Brainiac-5, and White Canary search for Kal and Lois' missing son Jonathan, Alex asks for Lena's help evacuating Earth-38's population before it's too late.
The subsequent complications from the Crisis leave Supergirl to face a chaotic threat.
As Supergirl tries to thwart a Toyman copycat, Winn Schott returns from the future.
Supergirl helps Winn face his greatest fear. After Alex sets out to find evidence against Lex, Brainy must decide between helping his friend or continuing to secretly work for Lex.
Mxyzptlk returns with a proposition for Kara – what if she could go back in time and tell Lena her secret before Lex did, would things turn out different? Looking back over key moments throughout the series, Kara must decide if she wants to change history to become friends with Lena again.