The novel starts in the early 1850’s in the USA. It opens with the conversation between the “kind” farmer from Kentucky, Arthur Shelby and the slave trader Mr. Haley. Mr. Shelby is in debts and has to sell some of his black slaves to cover his debts. Despite the fact that Mr. Shelby talks a lot about being humane to slaves he treats them more like pets than actual humans. He offers to sell his best slave - Tom, a kind-hearted man in his forties, who has a family on the farm - and Harry, the son of the young slave Eliza, the housemaid of his wife. Mr. Shelby is sincerely sorry and asks Mr. Haley not to punish the new slaves too much. He also decides to send Eliza somewhere when selling her child and, maybe, present her a new dress to avoid unnecessary tears.
Eliza herself accidentally hears the argument of Mr. and Mrs. Shelby afterwards. Mrs. Shelby tries to protect her housemaid, saying that she promised not to sell her child, but after all she obeys her husband. Eliza is desperate. Harry is her third child, another two she delivered died in infancy. She can’t lose the last child she has.
Her husband George Harris is a slave on the neighboring farm. He used to work in a factory and proved himself as smart, devoted and independent worker, but his self-confidence didn’t please his owner, so the farmer put Harris to the hardest work. That day George’s patience ended - his owner tried to force him to marry another slave, disregarding the fact that he and Eliza had church wedding. He decided to flee to Canada where he and his family won’t be slaves anymore.
He comes to his wife to tell her about his owner’s intentions, asking her to run as well to reunite with him in Canada. Eliza adds the horrible news she just heard, thus solidifying his decision to run. The woman tells Uncle Tom to run with them taking his family, or he and his wife and kids will never see him again. But Tom is ready to submit to his fate. He is too used to his slavery to run. Eliza and Harry run alone.
Their escape is revealed only in the morning. Mr. Haley, who already owns the mother and the son, sends his people to chase them. Eliza manages to cross the Ohio river, half-frozen, fast and deep. It is too dangerous for slave hunters to continue the pursuit. Eliza and Harry now are relatively safe in the North where slavery is forbidden.
Mr. Haley hires another hunter named Tom Locker to track them down and bring back. But Eliza is lucky enough to find people who are disgusted with the idea of slavery. They hide her and there mother and child are preparing to travel to Canada.
Meanwhile, Mr. Haley takes shackled Tom away from the Shelby’s farm. The eldest son of Mr. Shelby, George, can do nothing with it. He says tearful farewell to Tom, giving him a silver dollar to remember him, and swears that he won’t sell or buy slaves when he grows up.
Mr. Haley arrives to the city where the slave auction is held. He buys some more slaves, treating them like cattle, never bothering of keeping families together or somehow comforting them. All the slaves he bought are loaded to the steamship as cargo, shackled on the lower deck, while white people are on the upper deck, discussing the slave trade. Some of them believe that black people live better as slaves because they can’t care for themselves, others believe that slavery violates human feelings and some are certain that God created Africans to be slaves for the white people so it’s just natural order of things.
During one of the stops Mr. Haley buys a young woman holding a baby. He immediately sells the baby to another slave owner on the ship and the child is taken from his mother. In grief, she throws herself into the water and drowns.
A rich and noble gentleman from New Orleans named Augustine Saint-Clare travels by the same steamboat with his six-year-old daughter and an elderly woman. The girl is kind and curious and Tom is delighted to watch her play. Once the girl leans over the side too much and falls into the river. Tom jumps into the water and saves her. Grateful, Mr. Saint-Clare buys Tom from Mr. Haley immediately to be Eva’s (that is the name of the girl) personal guardian.
Augustine returns home, to the wealthy plantation in New Orleans. The woman travelling with him is his cousin, Miss Ophelia, the embodiment of accuracy and order. Her main virtue is the sense of duty. Ophelia comes to help managing the household because Mrs. Saint-Clare has weak health.
Marie Saint-Clare, the wife of Augustine and mother of Eva is an eccentric and selfish woman obsessed with getting all attention to herself. She sees slaves as inferior beings who exist for her whims only. Augustine, on the contrary, is relatively kind owner, who doesn’t make his slaves work too hard, allows them to have their own balls and parties and have a relatively normal life. Ophelia herself is from North, so she is disgusted with the very concept of slavery, but is too prudish to go as far as to say this aloud, because it’s inappropriate. The life of the Uncle Tom, now reading and playing with Eva, seems to get better. He really loves the girl and cares for her, so does Eva, deeply religious and very wise for her age.
In the meantime, Eliza is reunited with George, they both are sheltered by the Quaker community and prepare to flee to Canada together with their son. The black man named Jim joins them. He has long been living in Canada but returned to the United States to take his elderly mother with him.
Suddenly they realize that they are still chased. Tom Locker tracked them down and goes for them with two policemen and some of the locals. They start shooting but George shoots back injuring Tom. Other members of the chase retreat, but instead of leaving Tom to his death, George asks to pick him up and nurse the slave hunter back to health.
On the New Orleans farm the topic of slavery is still intensely discussed. Augustine disapproves slavery but admits that it will exist until the black people start to fight for their freedom, like other people all over the world. Ophelia still proclaims her idealistic beliefs and when Augustine’s patience ends, he brings her a gift, a slave eight-year-old girl named Topsy, brutally beaten and abused by her previous owner. Topsy is very smart, but hurt and delinquent, she is firstly presented as a thief and lover of cruel jokes that make Ophelia mad. Ophelia tries to formally discipline Topsy and educate her, without showing real feelings, but Topsy resists. It is Eva’s kindness and Tom’s care that help them open up to each other.
Finally Ophelia learns to care about the slave girl and Topsy reveals her sympathy and good nature hidden deep inside. Eva starts teaching Topsy and another slave, Mammy, to read and frequently discusses her Christian beliefs with Tom. But suddenly Eva falls ill, feeling weaker and weaker every day. She feels that her death is close and talks to her father, too seriously for a child. She asks him to free Uncle Tom after her death. Mr. Saint-Clare promises her this, and she dies in peace. All the family is devastated by this loss, because everyone, including the slaves, adored Eva. Topsy is crying near her bed and Ophelia tries to calm her down, acting more like mother then like owner. Only Marie is dramatically overreacting, trying to draw attention from the death of her child to herself, the mother in grief.
Augustine didn’t fulfill his promise. Soon after his daughter’s death he is also accidentally killed in the knife fight. Now the cruel Marie owns the mansion and she immediately sells it and all the slaves, leaving to her father’s land. She doesn’t want to hear Tom’s pleas about his former master’s will and sells him to the evil, violent and neglecting Simon Legree. Again Tom and other slaves find themselves in a warehouse treated as things, not people, like old furniture sold away from the house.
On the plantation belonging to Legree slaves live in miserable huts, so crowded that the people have no room to stand. They sleep on the ground on the thin layer of straw. The food is scarce and work is exhausting. But Tom still works hard and thoroughly and soon is promoted to the position of the leader of his barrack. However, his first task is to whip one of his fellow slaves. Tom refuses and he is stripped of his better food and clothes again and put on even harder work for his disobedience.
Once the beautiful quarterblood slave Cassie, who is Legree’s lover, comes to the plantation and starts collecting cotton with all other slaves. They are mocking her at first, considering that she traded her dignity for an easy life, but she works very fast, helping the weak and sick slaves. When Tom is whipped for refusing to whip another slaves, she comes to him and tends to his wounds. Cassie tells him her story: she was the daughter of a rich planter and received a good education. However, her father died suddenly and didn’t grant her freedom. She was bought by a young man who she loved very much. She had two children with him, but he made lots of debts and just sold her and the children away. Then there were other owners, lots of them, but heartbroken Cassie didn’t care anymore. Her children were taken away from her and she herself ended up here as a toy for Legree. He decided to punish her for a minor disobedience, sending her to the field for one day, but Cassie still has some influence on him, so she will try and persuade Legree to leave Tom alone, at least for the first time.
At the time Eliza, George and Harry are ready to move further. Tom Loker, who recovered and was shocked by George’s nobility and forgiveness, warns them that the ship they are going to board will be searched by detectives. Then Eliza dresses into a man’s suit, dressing Harry as a girl and joins Mrs. Smith, a white Canadian who returns home. They cross the border safely and stay at home of a local priest willing to shelter them.
Tom works hard on Legree’s plantation, still waiting for Mr. Shelby to find him and buy him back. Cassie offers him to kill Legree, but Tom believes that it’s not the Christian way. He also refuses to run with Cassie, who fell from grace and the new Legree’s mistress, young Emmelina. So they again run alone. Pretending they flee to the swamps, women hide in the attic that is believed to be haunted, so no one goes there to check. In an attempt to find the missing women, Legree orders his men to brutally beat and interrogate Tom.
In the last moment George Shelby, who was searching for Tom all that time, comes to Legree’s plantation. He is in time to see Uncle Tom, but can’t take him home - the slave is dying from his wounds. Tom manages to say a few words and then dies in George’s arms. At Tom’s grave George repeats his oath to never buy or sell slaves.
Taking advantage of the situation, Cassie and Emmelina run from the attic to the nearest steamboat. They meet George Shelby onboard and a woman called Madame de Tu who travels with her daughter. She happens to be the sister of George Harris. The young Shelby tells her the story of George and Elize and suddenly Cassie, accidentally hearing the talk, realizes that Elize is her own daughter, taken from her long ago.
On the ship, Emmeline falls in love with the member of the crew and they soon get married. Madame de Tu and Cassie go to Canada where the whole family is reunited. Later they decide to move to France. In France George Harris gets an education and moves with his family to Liberia, which he considers his homeland. Madame de Tu finds the second child of Cassie, who is also going to Africa.
Aunt Chloe, wife of Uncle Tom, starts working even harder after learning about her husband’s death. She doesn’t find a place for such a big grief in her life. George Shelby keeps his word and gives freedom to all his slaves.