George and Lennie get run out of their old town, Weed, because of Lennie's actions. He grabbed a girl's dress to feel it but he wouldn't let go. George and Lennie go to another town to start fresh and work on a ranch.
George and Lennie are greeted at the ranch by the boss, who is doubtful of their uncanny relationship. Later, the boss's son, Curley, picks a fight with Lennie because he does not like big people like Lennie. George gives Lennie permission to fight back, so Lennie crushes Curley's hand.
Curley's wife causes problems by visiting the ranch men, even if it's just because she's lonely. Carlson persuades Candy that shooting his old dog would be the best choice. Candy doesn't want to, but he finally allows Carlson to take the dog away to kill it. Candy soon regrets that he did not do it himself.
Lennie is in the barn with the puppy that Slim gave him. He is playing with him until he accidentally kills him by squeezing it too hard. Curley's wife enters the barn. Lennie starts touching her hair and his hand gets caught. She fights to get his hand out of her hair and Lennie snaps her neck, killing her.
Candy finds Curley's wife dead in the barn and goes to tell George and the other men that something has happened. They all go to check it out. Curley says that he will find Lennie and kill him himself, but George tells them that Lennie meant no harm. Everyone takes off to go find Lennie.
George meets Lennie at Lennie's safe spot, and explains their dream that they have together as Lennie imagines it. Lennie is happy as he thinks of tending the rabbits. As he is in this happy state, George decides to shoot him so that he can't hurt anyone again, and doesn't have to deal with Curley finding him.