On his Kentucky plantation in the 1840s, Mr. Shelby, a gentleman and farmer, discusses a debt he owes to Haley, a slave-trader. Haley presses Shelby to sell Uncle Tom, Shelby’s most trustworthy slave, and Harry, the fair-skinned child of Eliza, maid to Mrs. Shelby. Eliza is married to George Harris of another plantation, a fair-skinned slave who once worked in a factory where he showed great ingenuity. George has decided to escape, rather than waste his life laboring in the fields for his jealous master who removed him from the factory. Sometime after George has already left, Eliza overhears the Shelbys discussing Tom and Harry’s sale, and she and Harry flee toward Ohio, with the idea of reaching Canada.
Haley is furious at Eliza’s escape and attempts to track her, traveling with Sam, a cunning slave of Shelby’s. Sam manages to delay Haley. At the Ohio River, in the middle of winter, Eliza jumps with Harry from ice floe to floe and lands in Ohio. They are taken in by a Quaker family and reunited with George Harris, who has been traveling in the guise of a Spanish gentleman.
Uncle Tom decides not to try to escape; he sees it as his duty to be sold as his master intended. George Shelby, Jr., who loves Tom, sees him before the sale and promises to bring him back to Kentucky. Haley takes Tom on a steamboat down the Mississippi where they meet Augustine St. Clare, a wealthy man living in New Orleans with his daughter Evangeline, wife Marie, and a large group of slaves. Augustine has been in the North to fetch his cousin, Miss Ophelia, a stern, religious woman who is to help raise Eva, a religious and kind-hearted girl. Eva and Tom become friends, and Tom saves Eva when she falls overboard. St. Clare buys Tom.
George, Eliza, Harry, and others are shepherded by kind Quakers, including Phineas Fletcher, toward Sandusky, Ohio, on the lake bordering Canada. En route, two slave-catchers, Tom Loker and Marks, who are working for Haley, nearly corner the escaping party, but George returns a gunshot fired by Marks and hits Loker, who is pushed over a chasm by Fletcher and wounded. The slave-catchers flee, and George and his party carry Loker to recuperate in another Quaker home.
Uncle Tom is treated well at the St. Clare estate. He and Eva read the Bible to one another. Miss Ophelia takes a young slave girl, Topsy, under her care, but Topsy continues to misbehave. Eva’s health declines, though, and she announces she will soon return to her Father in heaven. Eva promises to love Topsy and asks St. Clare to promise that, after her death, he will become a practicing Christian and free his slaves. Eva dies, and St. Clare begins to carry out her wishes but, before he can, he is killed accidentally in a cafe fight. Marie does not honor her husband’s desire to free Tom, instead selling Tom to the cruel plantation owner Simon Legree.
Legree has also purchased Emmeline, a teenage slave girl, and on the Legree plantation near the Red River Uncle Tom meets Cassy, a once-beautiful slave. Legree puts Tom to work in the fields and asks him to whip a fellow slave in order to “harden” Tom. Tom says he will do anything his master says except hurt another human being. Legree and his overseers Sambo and Quimbo beat Tom mercilessly, hoping to crush his religious spirit. Inspired by Tom, Cassy and Emmeline plan to escape by storing materials in the attic, which they convince Legree is haunted, and hiding there after creating the appearance of escape through a swamp. They depart in earnest some days later. Legree takes his anger out on Tom, mortally wounding him.
Back in Ohio, Loker discovers he is being cared for by Quakers, despite his attempts to catch George and Eliza. He recognizes his past wickedness and repents. Meanwhile, the Harris family crosses to Canada by boat.
George Shelby, Jr. arrives at the Legree plantation and sees Tom before his death. Tom asks George to be a good Christian, and George swears he will never own slaves and will work to free them. On a boat back to Kentucky, George runs into Cassy and Emmeline. They meet Madame de Thoux, a wealthy woman revealed to be George Harris’ long-lost sister. This party, minus George, travels to Montreal, where the Harrises live. De Thoux is reunited with her brother, and Cassy is revealed to be Eliza’s mother.
George returns to the Shelby estate, frees his slaves, and declares that Uncle Tom’s cabin will always be a symbol of goodness and faith. Beecher Stowe closes the novel by swearing that its characters are based in reality, and that slavery is an un-Christian institution that must be eliminated.