Homegoing follows the descendants of an Asante woman in the 1700s named Maame. Maame has one daughter while enslaved in a Fante village and another daughter after escaping back to Asanteland; as a consequence, her daughters never meet. Effia, Maame's first daughter, is married to a white man who has come to Africa as part of the British slave trade, while her sister Esi, Maame's second daughter, is sold into slavery in the United States.
The chapters titled "Quey," "James," "Abena," Akua," "Yaw," and "Marjorie" follow the descendants of Effia. Effia and James Collins, the white, British man she is married to, have a son named Quey. Quey grows up in the Cape Coast Castle, where the white men live and where slaves are kept before being shipped away to the United States. He is educated in England and then returns to his mother's village to handle business negotiations with his uncle Fiifi. After Fiifi and other men from the village capture Nana Yaa, the daughter of the Asante king, Quey is married to the girl to form a political alliance. Quey and Nana Yaa have a son named James. When the Asante king, Nana Yaa's father and James's grandfather, dies, the family travels back to Asanteland to pay their respects. There, James meets a girl named Akosua and falls in love with her. James must return to his village and marry another woman named Amma Atta, but he fantasizes about running away and living a simple life with Akosua. When there is an attack on the place he is living, he sees his chance and runs away to Akosua, who has been waiting for him. They move away from her village and eventually have a daughter named Abena. Everyone in their new village thinks that they are unlucky because their crops grow poorly, and because of this Abena is never married. Her friend from childhood, Ohene Nyarko, promises to take her on as a second wife when a very prosperous year comes, but he breaks this promise after cocoa is successfully introduced to their village as a new staple crop. Abena, pregnant with Ohene Nyarko's child, flees to Kumasi, where there is a missionary church. She gives birth to a daughter named Akua there; Akua is raised for nearly all of her childhood by the missionary who lives there because, as Akua only finds out later in her life, the missionary accidentally killed her mother. Akua marries a man named Asamoah and goes back to his village, where they live with his mother and their three children. Akua repeatedly dreams about a firewoman, which leaves her dangerously tired during the day and often panicked at night. One night, she sets her family's hut on fire while she is asleep, killing her two daughters and burning her own body badly. Her husband, who lost a leg in a war, was only able to save their baby son Yaw, who is badly scarred. Yaw is sent away to be educated outside their village, and he becomes a teacher. He is always ogled because of his scars, and his anger and isolation because of this causes him to cut off ties with his mother. However, after he grows close to his house girl named Esther, he takes her back to his village and reconciles with his mother. Yaw and Esther move to the United States and have a daughter named Marjorie. Marjorie is very close to her grandmother Akua and loves to visit Ghana during the summer; however, she feels that she doesn't fit in fully in either Ghana or in America.
The chapters titled "Ness," "Kojo," "H," "Willie," "Sonny," and "Marcus" follow the descendants of Esi. Since Esi has been taken from Africa to the United States to be sold as a slave, her daughter Ness grows up on various plantations. She is taken from her mother at a young age, and as a young woman she is married to another slave from Africa named Sam, with whom she cannot communicate. They slowly fall in love and have a son named Kojo. Ness meets a woman named Aku who says that she may be able to get them out of slavery and to the north; when they try to escape, however, Ness and Sam are found. Aku takes Kojo to Maryland, where he grows up, gets a job on a boat, marries a woman named Anna, and has eight children. When the runaway slave laws come into effect, Kojo's wife disappears with their unborn son H. H works as a sharecropper as a young man until he is arrested and made to work for many years in a coal mine because he cannot make bail. He faces many hardships working in the mines, but when he finishes his sentence, he continues working in a mine as a free man. He marries a woman named Ethe who he had dated before getting arrested, and they have a daughter named Willie. Willie began dating a boy from her town named Robert when they were young, and they decide to move to New York together. They have a child named Carson and try to make a life together in New York, but the fact that Robert can pass for white drives them apart. Willie has a daughter named Josephine with another man named Eli who is a poet, and she gives up her own dream of becoming a jazz singer. Carson, who likes to be called Sonny from a young age, is a ladies man who has three children with three different women and works as a bartender at a jazz club. He gets in a relationship with a jazz singer named Amani and she gets him addicted to heroin. After a few years of spending all his money on dope, Sonny moves back in with his mother and gets clean. His son, Marcus, gets his PhD at Stanford studying black history, especially the story of his own family. He meets Marjorie, his distant relative, in California, and they return to Ghana together where they contemplate the past and face their fears.