The novel takes place in the California valley along the Salinas River. There are two settings for the action: the banks of the Salinas River and a nearby ranch. George Milton, small and smart, and his friend Lennie Small, a large man with mild retardation, are on their way to jobs at a ranch. They stop by the Salinas River to take a break from their long walk.
Lennie cannot remember where they are going, and George, annoyed, reminds him about their jobs. Lennie looks in his pocket for his work card and finds a dead mouse, which he found by the side of the road. Lennie likes to pet soft animals, like mice and puppies, but he is very strong and often kills his delicate pets. Lennie tries to hide his mouse from George, who demands it from him and throws it across the river.
That evening, Lennie goes to find his mouse, which makes George very angry. He argues with Lennie, but soon feels bad and tries to console him. George tells Lennie how one day soon they will own a farm of their own, where they will grow their own food and have rabbits Lennie can tend.
The next morning Lennie and George arrive at the ranch. The boss is annoyed because they have arrived late. The boss' son, Curley, is a small man who hates big guys like Lennie. He and George have a small confrontation. Soon after Curley leaves his wife enters. Her provocative dress and pose make George anxious. He warns Lennie to keep away from both Curley and his wife.
Two more workers, Slim and Carlson, come into the bunkhouse. Slim's dog just had puppies, and Lennie is anxious to have something soft to pet. Carlson suggests that Candy, an old man and fellow worker, kill his old smelly sheepdog and take one of Slim's pups.
Slim gives Lennie a pup, and he spends much of the evening out in the barn petting it. George tells Slim what happened at their last job. They were run out of town after Lennie unintentionally…