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Mary Smith flees a crisis at home in Manchester to stay with spinster sisters, Deborah and Matty Jenkyns, in the small rural town of Cranford. A new young doctor, Frank Harrison, comes to Cranford to join Dr Morgan in his medical practice. Frank, young and a bachelor, is the talk of the town.

Cranford's reigning aristocrat, Lady Ludlow, plans her annual garden party with her trusted estate manager, Mr Carter. The Jenkyns are intrigued when the house across the street is let to a retired soldier, Captain Brown, his daughter Jessie and Jessie's ailing older sister. Deborah and Matty are riveted to see that he seems acquainted with another local aristocrat, Sir Charles Maulver, who engages the Captain in an unknown business proposal.

Forced to assume responsibility for feeding his family, 10-year-old Harry Gregson sets off to poach to feed the others, however cold and exhausted, he becomes transfixed by Lady Ludlow's glasshouse and falls asleep. Mr Carter discovers him and is so moved by Harry's dismal poverty that he offers to pay Harry to run messages for him during the preparations for the garden party. Harry proves to be reliable, good-natured and intelligent, and Mr Carter offers to teach him to read and write. This is something to be done secretly, as he is fully aware that Lady Ludlow is passionately against educating the working classes.

Matty, meanwhile, is shaken as she encounters a secret visit from a mysterious acquaintance from her past, Thomas Holbrook. Rumours begin to circulate as news of a railway line, which will come right through Cranford, are heard. All the women are scandalised by this news, but none more so than Deborah, who sees Captain Brown's knowledge of the railway as the ultimate betrayal of a friendship.

When Dr Harrison's housekeeper, Mrs Rose, discovers a leg of mutton has been stolen from the kitchen window on the very same night that Mr Johnson, the owner of the town's most important store, is mugged, the ladies decide that a crime wave has hit Cranford.

Mr Johnson, meanwhile, becomes convinced that Job Gregson, the local ne'er-do-well, attacked him and Job is arrested. Job's son Harry decides to make a confession to Mr Carter of his own part in the poaching to save his father from transportation and has to bear the acute disappointment in him that Mr Carter feels. Mr Carter pleads Job's case with Lady Ludlow, saying that without her interference Job will be found guilty and the Gregson family will starve. Lady Ludlow is immovable; the Gregsons are not her responsibility.

Dr Harrison confides in his medical school friend Jack Marshland about his love for Sophy. Jack encourages him to send her some Valentine flowers. But Jack, a perpetual prankster, has set up some mischief by sending a Valentine card to Caroline Tomkinson as if from Dr Harrison, hinting at marriage. Caroline is ecstatic and eagerly awaits Dr Harrison's proposal.

Matty decides to confide in Mary about Mr Holbrook and how things were put asunder by a trick played by her younger brother, Peter, who then ran away in disgrace to India and has not been seen since.

Dr Harrison visits the rectory and formally asks the Reverend Hutton for permission to court Sophy. He promises he will propose as soon as he is able to provide a home for her.

At an auction, Dr Harrison bids for a small table. When he gets it home, he discovers it is a sewing table, so suggests his housekeeper Mrs Rose might like to use it. To Miss Pole and Mrs Forrester, this is tantamount to a proposal. Gullible Mrs Rose believes them and allows them to dye the grey out of her hair. They convince her that Dr Harrison will propose on May Day.

Finally, preparations for May Day excite everyone in the town. Everyone has high expectations of the day. Dr Harrison looks forward to the first time he and Sophy will be able to be together openly as a couple. The whole town gathers on the Heath.

Jem and Martha marry and live as lodgers in Matty's house - a source of joy for Matty. Miss Pole invites the ladies of the town to a secret meeting to discuss Matty's crisis. United in their love for Matty, they decide to secretly share part of their own incomes with her. Mary is recruited to devise a means of getting this to Matty without her knowing where the money came from.

Dr Harrison, on the other hand, is shunned by the town; no patients will come to him now that he has been exposed as a philanderer. He is encouraged to move on to start afresh somewhere he is not known. Mr Carter visits Capt Brown at the railway works in a desperate attempt to see if he can raise capital for Lady Ludlow's mortgage by selling timber or tools. While he is there, disaster strikes and the injured are taken to Dr Harrison's for emergency treatment. As Sophy's condition deteriorates, her young sisters defy their father and run to ask Dr Harrison to help. But has the call come too late?