George and Lennie have traveled together for many years since Lennie's Aunt Clara, who took care of him when he was younger, passed away. They grew up in the same town and were and still are friends. The book takes place during the Great Depression, so they are heading to a ranch to find work. They need a new job because Lennie got them fired from their last job in Weed.

     Lennie is the opposite of George. He's big, tall, and not very smart. George takes care of him. He feeds Lennie and gets him out of trouble when he does something bad, such as in Weed when he touched a girl's dress and the girl yelled out that he was assaulting her. Lennie likes to pet soft things. He often finds mice, which he tries to carry in his pocket so that he can stroke them with his fingers. However, when he tried to pet the woman's dress, she became upset, and Lennie and George had to hide in an irrigation ditch until the coast was clear.

     At the new ranch they are headed for, George wants Lennie to keep quiet. He doesn't want the boss to realize that Lennie has mental problems because then he might not want to hire him. They spend the night in the woods before they head to the ranch talking about their dreams for the future. They have often discussed the farm they someday hope to buy. They want to have chickens, cows, a little stove, and live off of the land. Lennie most looks forward to taking care of rabbits since they are soft. Before they go to sleep, George tells Lennie that if he gets in trouble again, he should come to this spot where they are sleeping and wait for George to get him.

     When they go to the ranch the next day, Lennie forgets his promise and speaks. Despite this error, they get the job. They work on Slim's team. Candy, the old, one-armed swamper shows them around followed by his even older dog. He shows George and Lennie the bunkhouse where they will sleep and tells them about Curley, the boss's son, who is a boxer whose wife lives with him in the boss's house. They meet Curley's wife, whom they learn is a tart who likes to give men the eye. When they find out Slim's dog recently had puppies, Lennie insists that George ask Slim if he can have one.

     Lennie adores his new puppy and often plays with it in the barn. One day when the men go to town to visit Susy's place for a bit of fun, Lennie is left behind and ends up talking to Crooks, the African American stable book who has a room attached to the barn. Crooks enjoys Lennie's company because he can say whatever he wants to him knowing that Lennie won't understand or remember. Then Candy joins them and begins talking to Lennie about their plan to buy a farm. Candy had offered George a substantial amount of money, most of which he received when he lost his hand, in order to go in with them on the purchase of a farm. All three of them were terribly excited at the prospect of leaving their jobs and living on their own by the end of the month. Crooks hears about their plan and offers his assistance, but then Curley's wife interrupts and points out how they are all lowly rejects who have been left behind by the other men. Crooks changes his mind and retracts his offer to join them on the farm.

     As always happens with the mice he finds, Lennie plays too roughly with the puppy and accidentally kills it. He is wondering what to do with the dead animal when Curley's wife comes into the barn. She begins talking to him about her past and her true feelings because like Crooks, she enjoys having someone listen to her for a change. The conversation reveals that she doesn't like her husband Curley, and she knows that Lennie is the one who broke his hand when Curley recently started a fight with him. Lennie tells her that he likes to pet soft things, so she allows him to touch her hair. As he continues to smash it, she becomes worried that he will mess it up, so she tells him to stop. Her fear causes Lennie to panic, cover her mouth, and then accidentally break her neck as he tries to stop her from screaming. Lennie remembers what George told him and goes to hide in the brush.

     George finds him hiding and tells Lennie he is not mad at him. George tells Lennie to look across the river as he describes their future farm to Lennie so that he can accurately picture it. As he speaks, George takes out the gun that he stole from Carlson earlier, and he shoots Lennie in the back of the head so that he dies instantly. This death parallels the earlier death of Candy's old dog which Carlson shot in the back of the head to put it out of its misery. George tells the men he had to shoot Lennie in self defense, but he knows that he really had no other option as Lennie could not take care of himself, could not be trusted, and would have otherwise been shot by Curley as revenge for killing his wife.