The story takes place in the town of P-, Kentucky. We first meet Mr. Shelby who is a poor man in danger of losing his farm. Mr. Shelby has to sell some of his slaves in order to get money so he does not lose his farm. He sells Uncle Tom and The Shelby's maid's son Harry to Mr. Haley. Mr. Haley is described as a harsh man who treats his slaves cruelly.
The Shelby's maid Eliza overhears the deal, and with encouragement from Uncle Tom she and her son Harry decide to flee to Canada for freedom. Mr. Haley rudely comes into the Shelby house and confronts them of helping Eliza and Harry Escape. The slaves are ordered by the Shelby's to get a horse ready for Mr. Haley. Comically the slaves put a beechnut under the saddle of the horse. Of course when Mr. Haley pursues to ride the horse, the beechnut bothers the horse, and Mr. Haley is thrown off.
Haley and his search party are invited to dinner and to relax before going out at the Shelby house. Sam, who is one of the slaves, had seen Eliza in the window and unintentionally drew attention to Eliza. She grabbed Harry and amazingly they crossed the Ohio River escaping from Mr. Haley and safely making it to the Northern border of Kentucky. Mr. Haley cannot cross the river and he retreats to the hotel. While at the hotel he runs into a man named Tom Loker whose job is to hunt run away slaves. Mr. Haley makes a deal with Loker for him to catch Eliza and Harry. Eliza and her son Harry travel and come across a Quaker village where they plead for help from the Quakers so Mr. Haley could not get them. Eliza's husband George meets them in the Quaker village and they are as happy as possible to see each other.
Uncle Tom is now being shipped on a boat with other slaves down the Mississippi River. He has finally earned the trust of Haley, for he has now earned the privilege to go anywhere on the boat. Uncle Tom, who keeps reading his Bible and using God for the reoccurring theme of persistence, He meets a little girl named Eva St. Clare. When Eva falls of the boat, Uncle Tom is the only person brave enough to save her. After he saves her she pleads to her father to buy Tom. Mr. St.Clare makes the deal with Mr. Haley and now Uncle Tom is property of the St.Clare's.
Tom has now been living with the St.Clare's for two years. The family has encountered many problems. Tom has taken the workload of the whole family under his wings. As time progresses Eva gets ill and slowly begins to die. The girl has greatly affected Tom's life, and with her death he feels like a part of him is missing. Next Mr. St.Clare becomes ill, and he dies leaving Marie in charge of the slaves. Marie sells the slaves off to a slave market, where Tom is picked up by another evil slave owner named Simon Legree.
One of the most brutal parts of the story is when Tom is ordered to whip a woman he helped fill her sack with cotton. Tom boldly denies Mr. Legree's order, and for doing that Tom is nearly fatally beaten by two men for his action. As time progresses the other slaves on Legree's plantation urge Tom to give in to Legree. Tom will not give up without a fight because he absolutely believes in God, and he is willing to do anything to do the right thing. After repeated beatings and lashings, last for what seems like an eternity, Tom is nearly dead.
Dramatically Mr. Shelby's son George comes and visits Tom, right as he dies. The slaves plead for George to help them escape but he can not so he offers them all of his help is abolishing slavery. Ironically George runs into two slaves who have escaped on a ship. He offers them protection, and while talking they realize the one woman named Cassy realizes that the description of Eliza may match the description of her daughter. Lastly the three travel to Canada where Eliza and her husband have safely arrived to have a happy homecoming with the two slaves George has met while on the ship.