The novel opens with a prologue set in 1938. A woman on a passing train spots a small blond boy in faded overalls waving near the Whistle Stop, Alabama, railroad crossing. She notices the boy appears to have an arm missing and looks for him every year afterward but never sees him again. This boy is Buddy Threadgoode Jr., the son of Ruth Jamison and the adopted nephew of Idgie Threadgoode, two women who ran the Whistle Stop Cafe in a small Alabama railroad town during the 1930s and 1940s.
Through flashbacks, newsletters, and present-day scenes, the novel traces the Whistle Stop community's intertwined lives across several decades. In the town's heyday, Idgie, a wild and spirited tomboy calmed only by her deep bond with Ruth, runs the cafe with Ruth and their cook, Sipsey Peavey. When Buddy loses part of his arm in a railroad accident, Idgie devotes herself to lifting his spirits. She shows him her secret bee tree, where she can plunge her arm into a hive without being stung. She also secretly obtains a three-legged dog from the River Club, a rough juke joint, to show Buddy that a missing limb need not hold anyone back. On Christmas Day 1938, Idgie gives the dog to Buddy, and the gift transforms him.
Idgie protects those she loves fiercely. When Arvel Ligget, a menacing man from nearby Pell City, threatens to kill her cat after harassing women in town, Idgie shoots him with a shotgun when he creeps up to the cafe one night. Sheriff Grady Kilgore, a lifelong friend, files it as accidental. But Idgie keeps a secret: Ruth had once left her over her drinking and gambling at the River Club and returned only after Idgie swore on the Bible never to go back. In 1935, Idgie stops at the club despite her oath and is goaded by Ligget into a poker game. She risks the cafe in a final hand and wins, taking a twenty-acre parcel of land. Terrified Ruth will find the deed, Idgie buries it in a mason jar at the base of her bee tree.
When Ruth dies of cancer in 1947, Idgie is devastated. She keeps the cafe open only until Buddy finishes college, then spirals into drinking and reckless driving. Her brother Julian persuades her to come to Florida, where she joins Alcoholics Anonymous and rebuilds her life, eventually becoming the mayor of Kissimmee. She sponsors others in recovery, including Jessie Ray Scroggins, a troubled preacher's son from Whistle Stop. Idgie dies peacefully in 1989 and is buried next to Ruth.
Buddy grows into a successful man. He becomes a one-armed high school football star, graduates near the top of his class at Auburn University, and builds a thriving veterinary clinic in Silver Spring, Maryland. He marries his childhood sweetheart, Peggy Hauck, and they have a daughter, Ruthie, named after his mother. Dot Weems, the former Whistle Stop postmistress, keeps the scattered community connected through annual Christmas letters.
The present-day storyline centers on Ruthie Caldwell, a widow in her early fifties living in Atlanta. As a young woman, Ruthie married Brooks Lee Caldwell, the son of one of Atlanta's wealthiest families. Brooks's mother, Martha Lee Caldwell, a snobbish woman who claims descent from English aristocracy, never fully accepts Ruthie, objecting to her family's small-town origins. After Brooks dies suddenly of a heart attack, Ruthie discovers they have little money; he had secretly taken out extra mortgages to keep the family business afloat. With both her children grown and gone, Ruthie feels purposeless and alone.
Bud, now in his eighties and widowed after Peggy's death from Alzheimer's disease, lives at Briarwood Manor, a senior community in Atlanta. In December 2013, he slips away on a church shuttle bus and boards a train to Birmingham, wanting to find Whistle Stop one last time. On the train he befriends Billy Hornbeck Jr., a young graduate student and grandson of the couple from the novel's opening scene, sharing stories about growing up at the cafe. When he arrives and searches for the town, it has vanished. He wanders into the woods along the railroad tracks, becomes lost, and spends the night under a tree, removing his prosthetic arm to sleep.
Ruthie receives a garbled phone call from Briarwood's assistant director who inadvertently makes her believe her father has died. After an agonizing period of grief, the director calls to clarify that Bud is merely missing. Police locate him the next morning, and Ruthie rushes to Birmingham. Bud is treated for hypothermia at a Birmingham hospital but is otherwise fine, though he has lost his prosthetic arm in the woods.
While Ruthie is in Birmingham, a local businesswoman named Evelyn Couch sees Bud's name on a television alert and contacts her. Years earlier, Evelyn's life was transformed by a friendship with Ninny Threadgoode, Idgie's sister-in-law, who left Evelyn a shoebox of old photographs. Evelyn shares these pictures with Ruthie, and the two form an immediate bond, eventually declaring themselves sisters.
Back at Briarwood, Bud adopts a stray orange tabby named Virgil and refuses to give him up despite the facility's no-animals policy. He calls a town hall meeting and argues that seniors need something alive to love and care for. The residents vote overwhelmingly to overturn the ban.
In December 2015, Evelyn reveals she has purchased the entire abandoned town of Whistle Stop and proposes that she and Ruthie restore the cafe and rebuild the community. Ruthie agrees, sells her Atlanta house, and moves to Birmingham. She surprises Bud with a visit to the site and gives him the key to Ninny's old house as a birthday present, telling him it will be renovated for him and Virgil.
The project stalls when a contractor discovers that a critical twenty-acre parcel between Evelyn's property and the interstate belongs to the estate of Arvel Ligget, whose heirs are locked in litigation. Without this land for road access, construction cannot proceed. Bud takes the news bravely but is crushed.
Then two boys stumble upon Bud's prosthetic arm under a tree near the railroad tracks. Nearby, searchers find an old mason jar containing a deed signed by Idgie, proving she was the true owner of the disputed parcel. She had won the land in the 1935 poker game and buried the deed at the base of her bee tree, the very tree where Bud unknowingly left his arm decades later. As Idgie's sole heir, Bud grants the right-of-way for roads and utilities, and construction resumes. He believes Idgie guided him to that tree and is still looking out for the family.
The town is rebuilt. Sipsey's granddaughter Alberta Peavey brings her grandmother's recipes to the cafe. Descendants of other original residents reopen the beauty shop and start a new congregation in the restored church. Bud elopes with Lois, a wealthy woman he met at Briarwood. Martha Lee, whose finances have collapsed and whose DNA test has revealed Chinese ancestry rather than the English lineage she claimed, arrives at the cafe seeking shelter. Ruthie's daughter Carolyn calls to say her husband has left her and asks to come to Whistle Stop, telling Ruthie for the first time that she needs her.
At the grand opening, the mayor of Birmingham declares July 28 "Whistle Stop Day," and every passing train blows its whistle. The cafe becomes a destination requiring reservations weeks in advance. In the epilogue, Bud and Lois plan a world cruise, while Ruthie thrives running the cafe, greeting customers and sharing the story of Idgie and Ruth. A retired widower from Birmingham has been visiting frequently, and Ruthie finds herself pleased by his attention. Her future, she realizes, is wide open.