Jojo is a 13-year-old biracial boy living in the fictional town of Bois Sauvage, Mississippi. He lives with his maternal grandparents, his mother, and his sister. Jojo's mother, Leonie, is a drug addict. When she is on drugs, Leonie is able to communicate with Given, the ghost of her dead brother. Given was murdered years prior in a racist attack by the cousin of her boyfriend Michael. His death was covered up as a hunting accident, and no one was criminally charged.
Because of her addiction, Leonie is frequently away from home and characteristically negligent. Jojo harbors feelings of resentment towards his mother, and he refers to her only by her first name. Jojo is the primary caregiver for his three-year-old sister, Kayla.
At the beginning of the novel, the audience learns that Jojo's grandmother, Mam, is dying of cancer. In addition, Jojo's father, Michael, is imprisoned at the Mississippi State Penitentiary (known as "Parchman"). On the evening of Jojo's birthday, the family receives news that Michael is being released from jail. When Leonie tries to tell Michael's parents the exciting news, she is chased from their property because she is Black. The next day, Leonie takes Jojo, Kayla, and her fellow bartender, Misty, to pick up Michael.
On the way to Parchman, Leonie and Misty decide to pick up meth from a supplier. The experience of picking up the drugs traumatizes Jojo, and his anger towards his mother further intensifies. While in the car, Kayla grows sick with a stomach bug and fever. Leonie tries to make an herbal remedy to ease Kayla's nausea, but she cannot remember the details that her mother taught her. Afraid that the remedy will poison Kayla, Jojo forces his sister to vomit.
When they pick Michael up from Parchman, Jojo encounters a ghost named Richie. Richie was imprisoned at Parchman with Pop many years ago. Richie tells Jojo that he died when he escaped Parchman, but he is unsure about the circumstances of his death. He follows Jojo to unearth the mystery.
While on their way back home, the family gets pulled over by a police car. Fearing Michael's re-imprisonment, Leonie swallows the entire dosage of meth. She grows violently ill in the car and has intense hallucinations. The family is free to go, and they arrive home to find that Mam's condition has worsened. Mam asks Leonie to collect offerings for her death so that she can pass peacefully. Meanwhile, Jojo discovers that Pop killed Richie in order to prevent him from being brutally lynched by a mob. Jojo sees the ghost of Given for the first time.
Mam dies, and Leonie has a difficult time dealing with her passing. Her drug abuse intensifies, and she leaves home for long periods of time. Jojo grows older and begins to develop some empathy for Leonie. He is able to speak with other ghosts, and he still remains in touch with Richie's spirit. One day, he sees Richie in a tree with other Black ghosts. Kayla sees them too, and she sings them off to peace.
