Set in the small town of Milledgeville, Georgia, in the 1950s, the novel weaves together the lives of several residents whose fates intersect around the fictionalized figure of Flannery O'Connor, the real-life Southern author who returned to her family's farm after being diagnosed with lupus, a chronic autoimmune disease.
The story opens on the night before the wedding of Cookie Himmel and Melvin Whiteson, a wealthy Manhattan banker. Flannery's peacocks, housed at her family farm Andalusia on the outskirts of town, scream through the night. Cookie tumbles out of bed and bruises her eye, and the noise goads the couple into consummating their relationship before the ceremony. At the wedding, Flannery, who walks on crutches due to lupus, jokingly offers them one of her peacocks as a gift. Cookie is visibly agitated, but Melvin, who has never heard of Flannery, senses a gap in his understanding of his wife and this town.
The narrative introduces Lona Waters, a quiet seamstress who treasures her solitary afternoons and secretly smokes marijuana, and her husband, Bill Waters, an ambitious police officer. Their daughter, Gigi, spends afternoons at the neighboring Treadle farm under the care of Miss Mary Treadle, a gregarious woman. Miss Mary asks Lona to employ her teenage son, Joe Treadle, as a sewing assistant, hoping work will draw the shy boy out of isolation. Lona agrees, mourning the loss of her free time.
At Andalusia, Flannery has been struggling with her second novel for seven years, channeling all her limited energy into writing. Her mother, Regina, a fiercely protective widow, monitors Flannery's health constantly. When Melvin visits to decline the peacock gift, the General, the largest peacock, spreads his massive tail in full display, leaving Melvin stunned. Flannery challenges Melvin about his decision to take a modest job at a local insurance office and asks him to give her weekly driving lessons, since her doctor has cleared her to drive but Regina opposes it. Melvin reluctantly agrees.
The lessons become a regular escape. Flannery asks about New York, where she lived before her illness, and Melvin shares that he left the city after his parents died. He begins secretly reading her fiction, and their conversations demand an honesty he finds nowhere else. He tells himself each lesson will be the last but keeps returning. Cookie eventually asks him to promise never to go back. Through flashback, the narrative reveals that Cookie believes the character Sabbath Lily in Flannery's novel
Wise Blood is a cruel representation of herself. Years earlier, at a high school ceremony, Flannery placed a cheap tiara on Cookie's head while presenting the Most Popular Girl award, advising the students to take "a good hard look" at who they are. This experience drove Cookie to flee Milledgeville for New York, where she spent three unhappy years before meeting Melvin.
Joe and Lona develop a working relationship built on shared silence. Over months, Lona becomes fascinated by the sadness beneath Joe's polite exterior. Joe impulsively kisses her on the back of the neck; she tells him to pretend it never happened, but the dynamic has shifted. Cookie becomes pregnant, and at the mayor's party, Flannery attends unexpectedly. Cookie freezes at Flannery's gaze and rushes outside to vomit. Melvin and Flannery share a long, silent look through the picture window, acknowledging everything between them.
Regina's Aunt Katie offers to fund a trip to Europe, including the miracle baths at Lourdes, France, on the condition that Flannery accompany Regina. Flannery objects to solicited miracles but keeps an open mind. She enters the baths and emerges still on crutches. Back in Milledgeville, Lona initiates a kiss with Joe in the Whitesons' nursery, and their affair begins. She establishes rules that erode over time. Joe and Lona eventually have sex in the guest room, declare their love, and plan to run away to New York.
Rose Whiteson is born, and Melvin stays away from Andalusia for 61 days, unable to resolve the conflict of bringing his daughter to the farm. When he returns, Flannery agrees to a real, public friendship. They share a peaceful moment on the porch with Rose lying on a blanket on the grass.
On the afternoon of the Children's Center opening ceremony, Cookie brings Bill to the Whiteson house to borrow a suit. Bill enters the guest room and finds Lona standing naked and Joe asleep on the bed. His hand jerks to his gun, and his sweating finger slips on the trigger. The gun fires, and Joe is shot in the chest and dies. The gunshot triggers panic among the birds at Andalusia, and in the chaos, the General tramples baby Rose on the lawn, crushing her organs. Melvin, on the porch with Flannery, cannot reach his daughter through the storm of beating wings.
The twin tragedies devastate every character. Melvin retreats behind drawn curtains. Cookie develops insomnia and begins doing jigsaw puzzles through the night, gluing each completed one so it cannot break apart. She starts experiencing violent shaking episodes. At Joe's funeral, everyone in the pew moves away when Gigi and Lona sit down; only Flannery crosses the church to sit beside Gigi. Flannery blames herself for failing to protect Rose and stops attending church. One night she encounters Cookie sleepwalking through town. Cookie tells Flannery she blames Melvin, not Flannery, for what happened.
Lona, Gigi, and Melvin all relocate to New York. Melvin establishes a rigid routine, avoiding all contact. Lona works as a secretary while Gigi peels potatoes at a restaurant and begins reading all of Flannery's published work. Cookie's mental state deteriorates: She returns to her old house one night and hurls rocks through the windows before being arrested. Her parents have her institutionalized. Flannery, whose lupus has been reactivated by surgery, visits Cookie in the hospital and apologizes for not sending Melvin away. Cookie asks if Flannery will write about what happened, and Flannery promises she will not. Cookie forgives her, and Flannery cries, a rare display that surprises them both.
Flannery's health continues to decline. She finishes her final story collection and receives last rites. When Melvin reads her obituary, he runs through Central Park until his body nearly fails. Lying on a mossy slope, he realizes he has wasted his life doing what he thought he was supposed to do instead of what he wanted. He travels to Milledgeville and begins visiting Cookie daily. A new doctor reduces her medication, and Cookie's clarity returns. Melvin proposes they start over together. Cookie agrees to think about it.
After Flannery's death, Regina agrees to let the peacocks be adopted by new caretakers. Miss Mary, who has been caring for Regina since Flannery's passing, meets Gigi at the Atlanta airport when the girl volunteers to supervise the relocation. When Miss Mary sees the thin, terrified girl, she throws her arms open, and Gigi falls forward into the embrace. At Andalusia, Melvin watches as men chase and net the peacocks. The birds scream with a force that reverberates across miles, reaching Cookie at the hospital window, Miss Mary and Gigi on the road, and, as if carried by some uncanny current, Lona on a New York sidewalk. As one man nets the biggest remaining peacock, the bird slowly shakes his tail free and spreads his feathers in a final, defiant display.