The story opens in Kentucky, where the well-meaning but indebted Mr. Shelby agrees to sell two of his slaves to a coarse trader named Haley: the trusted, deeply religious Uncle Tom, who manages the whole farm, and little Harry, the only child of the housemaid Eliza. The bargain is struck over wine in a comfortable parlor, and from that ordinary transaction the book's two great journeys begin.
Overhearing her son's fate, Eliza flees that night with Harry. Pursued to the half-frozen Ohio River, she carries him across by leaping from one cracking cake of ice to another, then is sheltered by Quakers and a wavering senator who cannot, face to face, send a mother back. Her husband George Harris, who has already declared that a slave has no country, escapes separately, and the family fights its way toward Canada and freedom.
Tom takes the opposite road. Sold down the river, he saves a drowning child, Eva St. Clare, and is bought by her father, a charming, skeptical New Orleans gentleman who sees the wrong of slavery clearly yet drifts without ever ending it. In that household Eva's tenderness and Tom's faith soften even the wild slave child Topsy, until Eva sickens and dies, and St. Clare, on the point of freeing Tom at last, is killed before he can sign the papers.
St. Clare's widow sells the slaves, and Tom passes to Simon Legree, a drunken planter on a remote Red River estate where labor is wrung out by the whip. Tom refuses to flog a fellow slave or to betray two women planning escape, and tells Legree that his master may own his body but never his soul. For that defiance Legree has him beaten until he dies, still forgiving the men who strike him; the young George Shelby arrives only in time to bury his father's old friend.
Around these parted fates Stowe weaves slave auctions, broken marriages, a mother driven mad by a sold infant, and Cassy's revenge on Legree, before reuniting the scattered Harris family in freedom. In a closing chapter she steps forward in her own voice to insist the incidents are drawn from life, to indict North and South together, and to urge her readers, above all, to feel rightly and act, lest a nation built on so great an injustice meet a day of reckoning.