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After Cliff Steele's body is destroyed in a car crash, Dr. Niles Caulder takes him in, builds him a new body, and introduces Cliff to three other "patients" whose ailments give them superpowers. When Niles goes on an expedition, the group decides to take a day trip into the nearby town but things don't go as planned.
Rita and Larry leave Cliff to find out what caused the destruction of Cloverton and the disappearance of Niles. However, Vic Stone--aka Cyborg--soon arrives with the flatulent donkey. They're sucked into the mystery and discover that Nobody is responsible.
The group heads for Paraguay by bus to follow up a lead on the donkey. Flit teleports Larry and Cliff there and they meet the man responsible for Morden's transformation into Mr. Nobody.
When he learns that the Unwritten Book is about to be read, ending the world, Willoughby Kipling comes looking for Niles but only finds the Doom Patrol.
To stop the Decreator, Nobody and Niles join forces to create its equal and opposite: the Recreator. Cliff gets a head in Nurnheim, and Rita and Elliot have a touching moment even though they don't touch.
Following Nobody's advice, Jane tracks down the 50s Doom Patrol, takes along Larry and Rita, and finds the team in a secluded home for teaching metahuman students. Vic is forced to call on Silas to help him repair, and Cliff gives Silas some fatherly advice.
A day in the life of the Doom Patrol, as Cliff suggests that everyone get together for group therapy. Rita remembers the first time she used her stage name, Larry chats with the Spirit, Vic reviews his dating app, Jane argues with herself, and Cliff visits an old friend.
Danny the Street sends a cake to Niles asking for his help, and Vic and Larry deliver it. Jane switches personas and invites Cliff and Rita to her wedding.
The Negative Spirit lets Cliff enter Jane's mind to discover why she's in a coma and to bring her out... if Cliff can survive.
The Bureau of Normalcy activates Ernest Franklin, aka the Beard Hunter, to find the missing Niles. When Ernest eats a strand of Vic's facial stubble, he becomes a match for Cyborg. Meanwhile, Nobody explores Niles' past and the woman that he protects.
When Cliff hears about Bump's death, he and Rita go to the wake at a bar in Florida so that Cliff can link up with his daughter Clara. Larry explores his past and meets an old friend, and Jane gets a lead to Flex Mentallo.
Silas asks for the team's help rescuing Vic from the Ant Farm. While imprisoned, Vic learns more about the AI rebooting in his head and meets his neighboring prisoner.
While Cliff and Jane try to restore Flex's memories, Larry and the Spirit come to an understanding. Vic tends to his injured father and Rita copes with her past.
The team finally try to track down Niles, and with some help from Flex enter White Space to confront Nobody. However, there's only one thing that will defeat Nobody, and only Nile knows it.
After Niles' revelation, the team goes its separate ways. However, circumstances bring them back together when Nobody, Ezekiel, and Whiskers join forces as the Brotherhood of Dangerous Animals.