Flagg's Fried Green Tomatoes at the Whistle Stop Café intertwines past and present, telling the story of a growing friendship between Evelyn Couch, a middle-aged housewife, and Ninny Threadgoode, an elderly woman residing in a nursing home. Evelyn visits Ninny weekly, listening to her recount memories of Whistle Stop, Alabama, where Ninny's sister-in-law Idgie and her friend Ruth operated a café. These tales, along with Ninny's companionship, help Evelyn embark on a more fulfilling life.

The novel begins with a 1929 column from The Weems Weekly, Whistle Stop, Alabama's local newspaper, announcing the opening of the Whistle Stop Café. The café is managed by Idgie Threadgoode and Ruth Jamison, with cooking by "two colored women," Onzell and Sipsey, and barbecue prepared by Onzell's husband, Big George. The story then shifts to December 1985, when Evelyn and her husband, Ed, visit his mother, Big Momma, at Rose Terrace Nursing Home in Birmingham, Alabama. While in the visitors' lounge, Evelyn meets Ninny, who starts sharing stories about the Threadgoode family. Flagg seamlessly blends descriptions of the past, drawn from Ninny's memories and columns from The Weems Weekly, with the evolving friendship between Ninny and Evelyn. Ninny reveals that she grew up near the Threadgoodes and married Cleo, one of their sons. Her stories often center on Idgie, who "used to do all kinds of crazy harebrained things just to get you to laugh."

Ninny shares with Evelyn the tragic death of Buddy, Idgie's beloved brother, and Idgie's kindness to hobos like Smokey Phillips, who frequented the café for a hot meal. When Idgie began selling food to Black customers at the back door, the local sheriff warned her that the Ku Klux Klan would target her if she continued. Nevertheless, Idgie refused to stop. At home, Evelyn reflects on her own life, feeling she has "lost along the way...The world had become a different place, a place she didn't know at all." Her sense of worthlessness and inability to stop eating lead to despair and suicidal thoughts.

In 1924, twenty-one-year-old Ruth arrived in Whistle Stop to oversee activities at the local church, and Idgie quickly developed a crush on her. During a picnic by a stream, Idgie was covered by a swarm of bees while extracting wild honey from a beehive. After the bees flew away, Ruth broke down in tears, fearing for Idgie's safety. Both confessed their love for each other, but Ruth decided to return home and marry her fiancé, Frank Bennett. Heartbroken, Idgie found solace with Eva, a woman Buddy had loved. At night, Evelyn imagines herself in Whistle Stop with all the characters from Ninny's stories, which helps her momentarily escape her troubles and find peace to sleep.