Two migrant workers, George and Lennie, have been let off a bus miles away from the California farm where they are due to start work. George is a small, dark man with "strong, sharp features". Lennie, his counterpart, is the opposite. He is a giant of a man with a "shapeless" face. Overcome with thirst, the two stop by a pool to camp for the night. As the two converse, it becomes clear that Lennie has a mild mental disability but is deeply devoted to George who cares for and protects him. Lennie loves to pet soft things but he often accidentally kills them. George notices that Lennie had been carrying and stroking a dead mouse. He angrily throws it away, fearing that Lennie could catch a disease from the dead animal. George complains loudly how much easier his life would be without having to care for Lennie, but the reader senses that their friendship and devotion is mutual. The two dream of farming their own land and much to Lennie's delight, keep rabbits. George then treats Lennie to a story that he's told many times of how life would be living in such an idyllic place.

The next day they arrive at the ranch. George is afraid of what they will think of Lennie so he tells him that he will do all the talking. He lies saying that they are cousins and that Lennie got kicked in the head by a horse as a child. They are hired and they meet Candy, and old handyman with one hand and an ancient dog. They also meet the boss's mean son, Curley. He just got married and is very possessive of his flirty wife. Curly is jealous and suspicious. Lennie thinks she is pretty but George warns her to stay away from her.

Then they meet Slim, the mule driver. Another worker, Carlson, suggests that they give one of Slim's puppies to Candy and shoot his old dog. George admits to Slim the next day that he and Lennie are not cousins, but friends since childhood, and Lennie often gets him into trouble. At their last job, he touched a woman's dress and was accused of rape. Slim agrees to give Candy a puppy. Carlson bugs Candy about getting rid of his dog. They tell him that death would be a relief to