Uncle Tom, the slave of Shelby Plantation, was loved by his master, their son and every slave in the plantation. He lived contentedly in their own cabin with his wife and children until Mr. Shelby, deeply in debt to a slave trader named Harry, agreed to sell his wife's servant Eliza's children Tom and Harry. Tom collapsed, but vowed that he would not run away, because he believed that doing so would make his master heavily in debt and he would be forced to sell all the slaves.

Just before Tom was taken away, Mrs. Shelby promised him that she would buy him back once she could raise money. Tom was sold to Harry, and Harry finally sold him to a kind master, Mr. St. Clare.

However, Eliza could not bear to be separated from her son and escaped the night before his son was taken away. She managed to escape to a Quaker villa, where there was a family that took in slaves. There, she was reunited with her husband George, who lived in a nearby plantation and escaped the cruelty of his master. The couple and their son spent the night with the Quaker family before returning to the underground railway.

Tom became friends with his new master, especially his little daughter Eva, who shared Tom's profound religious beliefs and piety. Eva hated cruelty and was finally conquered by the grief of slavery. When she became ill, she calmly accepted the impending death and told her family and their servants that she was glad to know that she would go to heaven, where such cruelty did not exist. St Clare began to face the reality. He thought slavery was evil. He promised Tom that if St Clare died, he would fill out a form to guarantee his freedom.