The novel begins with Truman Held visiting his longtime friend, Meridian Hill, in the small southern town of Chicokema. Meridian faces down the town’s army tank to allow black children to visit a small circus attraction. When Truman follows Meridian back to her house, he discovers that she’s extremely ill. She wears a railroad worker’s cap to hide her head, which is balding from her illness.
The first half of the novel tells the story of Meridian’s life in a non-chronological order, cutting from the past to the future and back again. Readers learn that Meridian grew up on a farm with an Indian burial mound, the Sacred Serpent, in the backyard. Her mother was strictly and devoutly religious, and she never forgave Meridian for refusing to accept the church. Meridian was never warned about the ways that girls can get pregnant, so she is surprised to find out that her high school boyfriend, Eddie, has impregnated her. She drops out of high school, gets married, and gives birth to a boy, Eddie Jr.
Meridian is not happy as a wife and mother. She doesn’t enjoy sex and her husband begins to cheat on her, eventually abandoning her completely. Stuck at home all day with the baby, Meridian begins to fantasize about killing the child or herself. One day, she sees a group of black men on television hosting a voter registration drive. Later in the night, the house where the drive was held is bombed, killing children who lived on the street. Meridian is intrigued by the voter registration drive and begins to get involved with the town’s nascent civil rights movement while a brother-in-law watches her child. She meets Truman Held and almost instantly feels attracted to him.
Because Meridian has the highest IQ in her high school, she is offered a scholarship to attend Saxon College in Atlanta. Meridian is determined to take advantage of the opportunity, even though she has to give her child up for adoption to do so. At Saxon, Meridian becomes friends with a bold, independent-minded girl named Anne-Marion Coles, and the two get involved with the Atlanta civil rights movement along with many of their classmates. Meridian works hard in college, but she is plagued by suicidal thoughts and guilt.
Truman attends a nearby college, and Meridian begins to fall in love with him. One night, they both go to a party where three white exchange students are in attendance. At the party, Meridian loses track of Truman and finally finds him flirting with these students. Afterwards, she doesn’t see Truman for months, when he has already begun dating one of the white students, named Lynne. When she finally sees Truman again, the two have sex, but Truman doesn’t use protection, and Meridian gets pregnant. She has an abortion and gets her tubes tied, without telling Truman. At the end of her senior year, she begins to suffer from a mysterious illness that causes blackouts and weakness; she is bedridden for months. Anne-Marion decides to end her friendship with Meridian.
After Meridian leaves college, she returns South, drifting from small town to small town. She steadily gives up her possessions and focuses on civil rights, helping other people, and getting people to register to vote. Meridian still suffers from her illness but often simply works through the pain. Everywhere she goes, she receives help from members of the black community who are grateful to her for her work in the movement. She continues to grapple with the questions of revolution that absorbed her in college.
The second half of the novel tells the story of Truman and Lynne, again told non-sequentially. After college, Lynne and Truman get married and move to Mississippi, where they initially live together happily. Although Lynne was involved with the civil rights movement in college, the mood of the movement is changing, and white activists such as Lynne are no longer welcome. In addition, because of the racist attitudes of the people in town, Lynne and Truman have to be careful about being seen together. Lynne often goes out with Truman and his friends, and this ends up having dire consequences.
One day when leaving a building, Truman and two friends are shot at by white assailants. One of these men, Tommy Odds, takes a bullet to the arm and ends up losing his forearm completely. After the attack, Tommy becomes bitter and grows to hate white people. He approaches Lynne at her home one day and begins to have sex with her, despite her protests. Because she feels guilty, Lynne doesn't struggle; the fact that Tommy was seen with a white woman probably motivated the attack. Afterwards, Lynne tells Truman and tries to leave him, but he refuses to talk about it. Truman begins sleeping in the community center, where he confronts Tommy one day; however, feelings of his own guilt overwhelm him, and he doesn’t hurt Tommy.
Left alone at home all day, Lynne begins to sleep with other black men to assuage her loneliness. She tells herself that these men love her, but eventually they all leave, until it is just Truman and Lynne again. Truman begins to leave Lynne for days at a time to visit Meridian, whom he believes he should have married. Finally, Lynne gets pregnant; she and Truman move to New York City, where they live in different apartments.
Lynne gives birth to a girl, Camara, who grows up in New York. When Camara is six, she is brutally attacked by white men and dies from her injuries. Truman and Lynne grieve separately, but both call upon Meridian, who travels across the city between their apartments, attempting to comfort them. In the aftermath of the tragedy, Lynne moves back South, and Truman goes to find Meridian in Chicokema.
The novel ends with Meridian and Truman living together, canvassing the town and countryside to get black men and women to register to vote. In the final scene, Meridian walks slowly away from her house, while Truman lies down in her sleeping bag to rest.
