Annie John chronicles the life of the main character, Annie John, from the age of ten until the age of seventeen. Annie John lives with her mother and father in a city on the island of Antigua. During her tenth year, Annie becomes obsessed with the idea of death after spending the summer outside the city near a cemetery and learning that children die. When she returns to the city, Annie starts stopping by funeral parlors just to watch mourners. One day, a young hunchbacked girl her age dies. Annie rushes from school to attend the girl's wake where she gets to view the dead girl's body. Later, she realizes that in her excitement she forgot to bring the fish home for dinner. She makes up a small lie, but her mother knows the truth. For her punishment, Annie is forced to her eat her dinner outside under the breadfruit tree.

Generally during summer vacation, Annie and her mother spend all their time together. Her mother lets Annie sleep in and then adds some hot water to the bath for her. Sometimes they even take a bath together after her mother adds herbs and spices that the obeah woman, a local healer, recommends. After the bath, they usually go to town where her mother teaches Annie how to shop and get the best products for the best prices. Annie thinks that her mother is very beautiful and very wise. Mrs. John grew up in Dominica but came to Antigua when she was sixteen following a conflict with her parents. Annie's father had children by other women too, and sometimes these women curse Mrs. John on the street. One day, Annie returns home and finds her parents making love in bed. She feels rejected when seeing them because she is not part of their union. In particular, she feels angry at her mother's neglect of their special relationship and starts to view her coldly.

When Annie starts school, she becomes best friends with Gwen. Annie is the brightest student in the class whose essay on the first day of school is praised. Although liked by the teachers, Annie also is popular with the students since she stands up for everyone, is good at sports, and makes rambunctious jokes when in private. Annie and Gwen walk to and from school together everyday. Annie tries to use their relationship to assuage her grief at being neglected by her mother, but it does not entirely work.

Annie eventually befriends the Red Girl, a tomboyish girl from a lower class who runs around dirty and disheveled. Annie admires her unstructured, carefree life and Annie starts to mimic her by playing marbles. Annie also begins a pattern of petty thievery to buy the Red Girl presents and lies daily so that she can meet up with the Red Girl after school. One day Annie's mother catches her coming out from under the house, where Annie hides her stolen loot. Her mother sees her with a marble and searches everywhere to find Annie's stash. Annie denies that she has any other marbles despite her mother's entreaties and takes pleasure in her mother's inability to find them. Eventually, Annie starts to menstruate and the Red Girl moves away, so Annie stops playing marbles altogether.

Annie's good grades make her the prefect of her class, despite her occasionally mischievous behavior. One day during a history lesson, Annie grows bored because she knows the material and starts reading ahead in her book. She finds out that Christopher Columbus was imprisoned later in his life for having offended the Queen. Annie sees a picture of him in chains and writes under it, "The Great Man Can No Longer Move," a phrase that her father once used to describe her grandfather. Her teacher, Miss Edward, sees her and upbraids her for blasphemous behavior. Annie is sent to the principal who takes the prefect position away from her and orders her to copy Book I and Book II of Milton's Paradise Lost. After her scolding, Annie returns home hoping that her mother will cheer her up, but her father and mother seem too absorbed in each other to notice her distress. Furthermore, her mother tricks her into eating breadfruit, something Annie detests, by making it look like rice. When faced with her mother's betrayal, Annie feels complete hatred for her.

Annie's unhappiness comes to resemble a heavy black ball inside her that is covered with cobwebs. Annie cannot easily say what caused this ball but it makes her feel miserable all the time. Her success continues at school and she is promoted into a class with much older girls. Annie feels socially isolated and even finds Gwen to be a dull companion. Annie dreams of moving to Belgium, a place that Jane Eyre visited, so that Annie's mother can no longer find her. One day after school, Annie avoids Gwen and heads into town instead. Annie stares at her reflection in a store window and feel overcome by sadness at seeing herself look so ugly and ragged. A group of boys nearby starts teasing her and she speaks to one of them since she knew him as a child. When they keep laughing at her, she goes home. Her mother confronts her in the yard and tells Annie that she saw Annie's flirtatious behavior in town. After her mother calls Annie a slut, Annie loses her temper and says, "like mother, like daughter." Her mother then says that she always loved her best until that moment. Annie senses that something dark has come between them. At dinner that night, Annie tells her father she wants her own trunk like the one that her mother has.

Annie suffers a mental breakdown that coincides with a three-month rainstorm and becomes bedridden. In her sickness, her behavior reverts to that of an infant. She cannot be left alone, she wets her bed, and she needs help eating. Both the local doctor and an obeah woman treat her, but she remains ill. Eventually, her grandmother, Ma Chess, comes. She heals Annie not with her powerful knowledge of obeah, but from holding her throughout the days. After Annie is better, they notice that she has grown even taller than she was. She has to get a new set of clothing before returning to school.

Finally, Annie turns seventeen and decides to leave Antigua to study nursing in England. Now she looks forward to living a separate life and being away from her mother. As she walks to the boat with them, she remembers her young life with its warmth, but acknowledges that there is no space left for her at her parents' house. Her parents wave goodbye as she disappears on the boat and Annie lies in her cabin with expectations of the future.