The complete title of Uncle Tom's Cabin is Uncle Tom's Cabin; or, Life Among the Lowly.
The book opens with Arthur Shelby facing the loss of his Kentucky farm because of debts. Even though he and his wife Emily have a benevolent relationship with their slaves, he decides to sell two of them to a slave trader: middle-aged Uncle Tom, who has a wife and children, and Harry, the son of Emily's maid Eliza.
When Eliza overhears the Shelbys discussing plans to sell Tom and Harry, Eliza runs away with Harry, leaving a note of apology to her mistress..
Uncle Tom is sold and placed on a riverboat which sets sail down the Mississippi. While on board, the slave meets and befriends Eva, a young white girl. Eva falls into the river and Uncle Tom saves her. In gratitude, Eva's father, Augustine St. Clare, buys Tom from the slave trader and takes him to his family home in New Orleans. Uncle Tom and Eva become close because of the deep Christian faith they share.
During Eliza's escape, she meets up with her husband George Harris, who had run away previously. They decided to try to reach Canada but are now being tracked by Tom Loker, a slave hunter. Loker and his men eventually trap Eliza and her family, prompting George to shoot Loker. Concerned that Loker may die, Eliza convinces George to bring the slave hunter to a nearby Quaker settlement for medical treatment.
Back in New Orleans, St. Clare debates slavery with his Northern cousin Ophelia who, while opposing slavery, is prejudiced against blacks. St. Clare, however, believes he is not biased, even though he is a slave owner. In an attempt to show Ophelia that her views on blacks are wrong, St. Clare purchases Topsy, a young black slave and asks Ophelia to educate her.
After Uncle Tom has lived with the St. Clares for two years, Eva grows gravely ill. Before she dies she experiences a vision of heaven which she shares with the people around her. As a result of her death and vision, the other characters resolve to change their lives, with Ophelia promising to throw off her personal prejudices against blacks, Topsy saying she will better herself, and St. Clare pledging to free Uncle Tom.
Before St. Clare can follow through on his pledge, he dies after being stabbed while entering a New Orleans tavern. His wife reneges on her husband's vow and sells Uncle Tom at auction to Simon Legree, a vicious plantation owner who takes him to rural Louisiana where Uncle Tom meets Legree's other slaves, including Emmeline.
Legree begins to hate Uncle Tom when he refuses Legree's order to whip a fellow slave. Legree beats Uncle Tom viciously. He resolves to crush his new slave's faith in God, but Uncle Tom refuses to stop reading his Bible and comforting the other slaves. He meets Cassy, another Legree slave who had been separated from her son and daughter when they were sold. Unable to endure the pain of seeing another child sold, she had killed her third child.
Meanwhile, Loker has changed as the result of being healed by the Quakers. Eliza and Harry have obtained their freedom after crossing into Canada. Back in Louisiana, Uncle Tom almost succumbs to hopelessness as his faith in God is repeatedly tested by hardships on the plantation. He has two visions, one of Jesus and one of Eva, which renew his resolve to remain a faithful Christian. He encourages Cassy to escape, which she does, taking Emmeline with her. When Uncle Tom refuses to tell Legree where Cassy and Emmeline have gone, Legree orders his overseers to kill Uncle Tom.
As Uncle Tom lays dying, he forgives the two overseers who savagely beat him and both men, humbled by the character of the man they have killed, become Christians. George Shelby, Arthur Shelby's son, arrives to buy Uncle Tom’s freedom, but finds he is too late.
On their boat ride to freedom, Cassy and Emmeline meet George Harris' sister and accompany her to Canada. Once there, Cassy discovers that Eliza is her long-lost daughter who was sold as a child. Now that their family is together again, they travel to France and eventually Liberia, the African nation created for former American slaves. There they meet Cassy's long-lost son. George Shelby returns to the Kentucky farm and frees all his slaves. George tells them to remember Uncle Tom's sacrifice and his belief in the true meaning of Christianity.