The story returns to the Shelby plantation, where Mr. Shelby, who was dreadfully ill, has died and transitioned the care of his estate to his wife. Since his death, Mrs. Shelby has taken care of the plantation's finances; after receiving Miss Ophelia’s letter about Tom, she had intended to buy him back. Unfortunately, the letter was late by a few months, and by the time Tom's family got the news, he had already been sold to Legree. 

Master George goes to New Orleans for business and decides to look for Tom while he's there. He finds out that Simon Legree bought Tom and goes to the Legree plantation, where he finds Tom on the brink of death. He tries to convince Tom to come back to Kentucky, but Tom argues that it is too late for him to return to his family. As he dies of his wounds, he declares a spiritual victory over Legree and the entire institution of slavery. 

Enraged by the animalistic cruelty with which Legree treated Tom, Master George hits him, then carries Tom’s body away and buries him outside of the plantation. When Legree's slaves see how much Master George cared about Tom, they beg him to buy them. Knowing that he cannot buy every single slave that suffers under cruel masters, Master George swears on Tom's grave that he will do everything he can to put an end to slavery.

After Master George buries Uncle Tom and leaves, the house servants on the Legree plantation start to hear strange whispering and groaning coming from inside the house. Legree knows what they are afraid of, which makes him even more scared. He locks his bedroom door, drinks a lot, and has more bad dreams. 

In one of his nightmares, Legree sees his mother's shroud, which is the sheet she was buried in. But then Cassy shows up in the dream with the same shroud. When Legree wakes up, a figure in a white cloak stands in front of him and says, "Come, come, come." The person walks away, and Legree tries the door, but it is locked. After that, people start to say that Legree is sick and dying because he has had too much to drink and is seeing things. Some servants later see two people in white veils—who readers know to be Cassy and Emmeline—walking away from the plantation on the main road.

Later, Cassy and Emmeline dress up as a Spanish woman and her maid and board a boat headed north. Master George, who is heading back to Kentucky with the awful news of Tom’s death, is also on the same boat. Cassy and Master George get to know each other, and Cassy eventually tells Master George that she and Emmeline are fleeing Legree. Master George pities the freedom seekers, knowing what they have likely endured. 

Master George also meets a French woman named Madame de Thoux who is going in the same direction. Master George is going to Kentucky, so Madame de Thoux asks him if he knows George Harris. Master George tells what he knows about him. He talks about how Eliza married him and then ran away to Canada. Madame de Thoux shocks everyone by saying she is George Harris's long-lost sister Emily. She had been sold to someone in the south, but she later married her owner and moved to the West Indies, where her husband eventually died, leaving her immense wealth.

Cassy overhears some of their conversation and asks Master George to tell her more about Eliza and where she came from. Master George tells her all he knows, and Cassy is stunned, realizing that Eliza is her long-lost daughter.