Uncle Tom’s Cabin opens as Mr. Shelby and a slave trader, Mr. Haley, discuss how many slaves Mr. Shelby will need to sell in order to clear up his debt. Despite his misgivings, Mr. Shelby decides to sell Tom, a faithful and honest man, and Harry, the son of his wife’s favorite slave, Eliza.
Eliza overhears that her son has been sold and makes a split-second decision to take him and run away to Canada that very night. Earlier that day, her husband, George Harris, had let her know that he planned to leave his own master, and she hopes they will both be able to escape and reunite in Canada.
As Eliza takes off, the slave trader Mr. Hadley follows her and almost catches her. She escapes into Ohio by crossing a river on a piece of floating ice. Mr. Haley sends slave catchers after her, and returns to collect his remaining property, Tom. Tom chooses not to run because he knows his master (at this point, Mr. Shelby) relies on his honesty.
Tom and Mr. Haley leave for the South. En route, Tom saves a little girl from drowning. The girl's father decides to buy Tom to be his daughter's personal servant. Tom has lucked out (insofar as being sold can be called lucky) because the girl’s father, Augustine St. Clare, treats his slaves relatively well. The little girl, Eva, is also a sweet child, devoted to her servants and family. Unfortunately, the mother, Marie St. Clare, is a more typical slave owner and runs her slaves ragged as they try to satisfy her endless demands.
Tom grows fond of little Eva. They discuss their mutual Christian faith on a daily basis. Eva even transforms the life of a hardened young slave girl named Topsy, and begins to teach another slave, Mammy, to read.
When it is clear that Eva is ill and going to die, she calls all the slaves together to give them a speech about God’s love (and her love) for them. She gives each slave one of her blonde curls so they will remember her. Then she dies of consumption (known now as tuberculosis).
Meanwhile, Eliza and her husband George are reunited in a Quaker camp. From there, they escape to Canada successfully, though not without a couple of run-ins with slave catchers on the way.
Back at St. Clare household, Augustine St. Clare is heartbroken at his daughter Eva’s death, as are all the slaves. St. Clare promises Tom his freedom but, before he finishes making out the papers, he is killed in a barroom brawl. Tom is sold at auction, along with many of the other St. Clare slaves.
Tom’s new master is Simon Legree, an evil and violent man who works his slaves until they die, then buys new ones cheaply in a never-ending cycle. Despite Legree’s treatment, Tom maintains his honest, kind behavior. Legree does his worst to "harden" Tom so that he can use Tom as an overseer on the plantation, but Tom refuses to change no matter how hard or how often Legree beats him.
When Tom encourages two female slaves, whom Legree uses as prostitutes, to escape, Legree beats Tom to death. It takes a few days for him to die, however, and in the meantime, his old master’s son, George Shelby, arrives to emancipate (or free) Tom – too late. Instead, "Master" George buries Tom then leaves.
The two female slaves who escaped Legree’s house, Cassy and Emmeline, end up on the same ship as George Shelby. Cassy confesses her story to him, realizing that George’s heart is soft towards the plight of escaping slaves. Another woman on the ship soon confesses her story to George as well, and it turns out that she is George Harris’s sister, sold south into slavery many years earlier.
George Shelby relates that George Harris married Eliza and they both escaped to Canada. Cassy, overhearing the story, puts two and two together and realizes that Eliza is her own daughter, who was taken from her many years before.
The two women travel to Canada together and are reunited with their families. Although Tom’s life ended in tragedy, there is much happiness among these slaves who survived and escaped the trials and tribulations of slavery, either through emancipation or by fleeing to Canada.