Throughout the novel the narrator and time period change, and the reader relies on the chapters' headings to establish the date and the source of the chapter. Some of the narration comes in the form of the fictional newsletter called "The Weems Weekly"; other narrations come from the Couches' house in Birmingham, and omniscient narrations reveal still more. The framing story, set in the mid-1980s, depicts Evelyn Couch, who goes weekly with her husband to visit his mother in a nursing home. On one visit, Evelyn befriends Ninny Threadgoode, another resident of the same home, who tells Evelyn stories of her youth in Whistle Stop in the 1920s. Between subsequent visits, Evelyn assumes the protagonists of these stories as rôle-models.
According to her own account, Ninny was an orphan raised by the Threadgoodes, and eventually married one of their sons; but the principal character of most of the story, is the youngest daughter, Idgie (Imogene) Threadgoode: an unrepentant tomboy, encouraged by her brother Buddy. When Buddy is killed by an accident on the railway, Idgie secludes herself, until Ruth Jamison comes to live with the family while she taught at the Vacation Bible School, and Idgie becomes enamored of her. Idgie is again saddened when Ruth leaves to marry her fiancé, Frank Bennett. After the marriage, Frank is often cruel to Ruth; but she remains faithful to him until her mother's death. Subsequently, Idgie receives a message from Ruth, and rescues her, with the help of her friends and surviving brothers. Intimidated by Big George, the family's handyman, Frank does not resist. With money given by her father, Idgie establishes the Whistle Stop Cafe, with Sipsey (George's mother) and her daughter-in-law Onzell as cooks, and becomes secondary guardian to Ruth's son, Buddy Jr. (known as 'Stump' for the loss of an arm in a railroad accident). The café quickly became known all over the U.S. during The Great Depression due to the communication between various hobos fed there, of whom the most recurrent is 'Smokey Lonesome' Phillips. Ruth dies due to cancer, leaving Idgie heartbroken yet still visiting her grave decades later as seen by Evelyn at Easterone year. After the railroad yard closes, the cafe (and ultimately the town) ceases operation. Several years later, Idgie and Big George are arrested for the murder of Frank Bennett; but the case is dismissed at the trial when the local minister, repaying Idgie for helping his son, testifies (falsely) that she and Big George were at a three-day revival when Frank Bennett went missing. Bennett's body was never found, but it is revealed toward the end of the novel that he was killed by Sipsey in the attempt to claim Stump, and his remains largely cooked by George into barbecue sandwiches, fed to the detectives in search of Frank himself. Stump grows to manhood, and recounts stories of his guardians to his daughter and granddaughter; and George's sons, Jasper and Artis [sic], achieve careers as their own: Jasper as a Sleeping Car Porter, and Artis as a gambler.
Inspired by these stories, Evelyn gets a job with Mary Kay Cosmetics and, at Mrs. Threadgoode's suggestion, starts to take hormones for menopause, and confronts various long-held fears. She becomes happier than she ever has been. When on vacation for her health, she receives a letter from Mrs. Hartman, Mrs. Threadgoode's neighbor, that Mrs. Threadgoode has died, and left various trinkets for Evelyn. The end of the novel reveals that Idgie and her brother Julian, after the depopulation of Whistle Stop, are operating a roadside food-stand in a location undisclosed.