Of Mice and Men is the story of two Depression-era migrant farm workers, George and Lennie. As the book opens, they are walking to a ranch in the Salinas Valley, California, where new jobs await them. It quickly becomes clear that Lennie has a mental disability. He also likes touching soft things; when they stop for a rest George finds that he has been carrying and stroking a dead mouse. Over supper, at Lennie’s request, George recites an often-told plan for the two of them to get their own place and “live off the fatta the lan’.’’

The next day, the two men report for work at the ranch. They make friends with Candy, a kind old “swamper” (handyman), and Slim, a respected ranch worker. Curley, the boss’s jealous and mean-spirited son, takes an immediate dislike to them. Lennie thinks Curley’s flirtatious new wife is “purty,” but George warns Lennie to stay away from her. When Candy overhears George and Lennie talking about their dream farm, he offers to put his savings towards it and form a partnership with them. Suddenly their dream seems achievable for the first time. 

George reveals to Slim that Lennie has often gotten them into trouble. In fact they had to flee their last job because Lennie clung on to a woman’s dress and was accused of rape. Slim agrees that Lennie “ain’t mean” and he offers to give him one of his dog's new puppies.  

Curley picks a fight with Lennie, who doesn’t seem to know his own strength and crushes Curley’s hand in self-defense. Soon afterwards, Lennie accidentally kills his puppy while petting it. Curley’s wife consoles him. Lennie tells her that he loves to pet soft things, and she offers to let him feel her hair. When he grabs it too tightly, she cries out; in his panicked attempt to quiet her, Lennie accidentally breaks her neck.

Realizing he “done a bad thing,” Lennie flees to a pre-arranged emergency meeting place where George soon joins him. Meanwhile the men back at the ranch assemble a lynch mob. To Lennie's surprise, George does not seem angry. He starts to tell the story of the farm they will run together. As he describes the rabbits Lennie will tend, the sound of the approaching lynch mob grows louder. While Lennie listens to the story of their dream farm, George shoots his friend in the back of the head.