Section 1
George and Lennie are in California and is on their way to a ranch by a river. While on the way, George discovers that Lennie is holding a dead mouse. Lennie protests that it is not his fault the mouse is dead but George takes the mouse and throws it into the river. During the conversations between Lennie and George, the readers learn that Lennie has a mental disability. George tells Lennie how to behave when they meet their boss. He does not want Lennie to talk or else they will learn of his disability and it could cost them their jobs. George decides to camp out for the night and to continue the next day. While George prepares the beans, Lennie jumps in the river to retrieve the dead mouse but George finds and throws away the mouse again. In the past, Lennie killed mice that was given to him by his Aunt Clara because he could not control his strength when he pets them. As they both eat their beans, Lennie wishes for ketchup to go with his beans. George becomes angry and rants about how his life would be better without Lennie. He explains how in their last town, Lennie grabs a girl's dress because it looked soft and does not let go. She screamed and the locals think Lennie has assaulted her. George and Lennie had to run away and get out of town. After, Lennie says he would leave George alone and live by himself but George protests and says he would be lonely without Lennie. George apologizes by telling Lennie's favourite story which is their dream. Their dream is to own land and a farm and to live “live off the fatta the lan’.”
George tells Lennie that if he gets into trouble at the ranch, he should return to this place and hide in the bushes.
Section 2
The next day, George and Lennie finally make their way to the ranch and their bunkhouse where they meet Candy, an elderly man who had lost his right hand in an accident while working. They also meet with the boss of the ranch and explain why they're late.When the boss asks about their work experience, George speaks for Lennie to prevent him from finding about Lennie's disability. Unfortunately, Lennie speaks and the boss becomes suspicious. George says that Lennie is his cousin and was kicked in the head by a horse as a child. The boss assigns them to work under a man named Slim. When the boss leaves, Candy overhears George telling Lennie that he is glad they're not related. Soon, Curley, the boss' son, enters the room and asks if they've seen his wife. He is an ex-boxer and does not like Lennie because of his size. Curley leaves and George tells Lennie to stay away from Curley. Curley's wife appears outside asking for her husband and flirts with Slim and the other men. George also tells Lennie to stay away from Curley's wife. Slim and Carlson enters the bunkhouse and Carlson asks about Slim's dog who had just given birth to nine puppies. Unfortunately, Slim had to drown four puppies because their mother would not be able to feed them all. Carlson also asks Candy to shoot his dog because it is old, smelly, and useless. Curley appears and again asks for his wife.
Section 3
It is now the end of the workday. Slim agrees to giving Lennie a puppy. George and Slim are playing cards and George tells Slim about his past with Lennie. George reveals that he used to bully Lennie. One time, he asked Lennie to jump into a river and he did and almost drowned because he didn't know how to swim. After that, George had stopped bullying him. Carlson tries to persuade Candy to shoot his old, useless dog again. He pressures him and Slim also agrees. Carlson takes Candy's dog outside, shoots him and buries him. The guys invite George to a whorehouse and they compare two different whorehouses. Lennie asks George to tell him his favourite story again. Candy hears and wants to join in on their dream. He is afraid that because of his old age and handicap, the will have to let him go. Candy is willing to pay part of the land with his life savings. Their dream is now much closer and seems much more realistic. Curley appears and sees Lennie smiling and thinks he is laughing at him when he is only thinking of the dream. Curley is enraged and fights with Lennie. Lennie does nothing but cry out as Curley throws his punches. George tell Lennie to get him and Lennie crushes Curley's hand. Curley does not get Lennie and George fired because he would be the laughingstock of the ranch.
Section 4
It is now the next evening. Crooks, a black man with a crooked back is sitting in his home. He is excluded from everyone because of his skin colour. Lennie appears and wants to come into Crook's home. Crooks refuses and says if a black man is not allowed in a white man's home, then a white man is not allowed in a black man's home. However, Crooks is overcome by loneliness and lets Lennie in. Lennie reveals his and George's dream of owning land. Crooks begins to play with Lennie by saying what if George does not come back. Lennie becomes angry and threatens Crooks but Crooks quickly says George is not hurt and is coming back. Candy joins them and they continue to talk about the dream. Curley's wife appears and talks about her loneliness and her unhappy marriage but Candy and Crooks wants her to leave. She reminds them of her power to fire them because of her position. She leaves and the men return from the whorehouse.
Section 5
Lennie is in the barn stroking his dead puppy. The puppy had tried to bite him and Lennie hit the puppy, accidentally killing it. He does not want to tell George because he thinks George would not let him handle the rabbits when they own a farm. Curley's wife enters the barn and talks to Lennie about her loneliness and her dreams. Lennie talks about rabbits and says he loves to touch soft things. Curley's wife offers Lennie to touch her soft hair. He holds her hair too tight and she yells. Lennie panics and tries to silence her and he accidentally breaks her neck. He realizes what he has done and runs to the forest by the river to hide in the bushes as George had instructed. Candy discovers her body and calls George. Candy asks George if they can still buy the farm but knows it is now impossible. George does not want the other men to think he had something to do with her death so he instructs Candy to call them while George pretends he did not know. Everyone arrives and sees the body. Carlson's gun in missing and is thought to be stolen by Lennie. Curley wants Lennie dead and fetches Crook's shotgun. They all go after Lennie.
Section 6
Lennie is hiding and visions of his Aunt Clara appear. She lectures Lennie for not listening to George and causing problems for him. Another vision of a large rabbit appears and says that George will abandon and beat up Lennie. George appears but he is not a vision. Lennie asks George to tell the story of their farm. George asks Lennie to look across the river while he is telling the story. As he talks about their dream, he raises Carlson's gun and shoots Lennie in the back of the head. The other men appear at the sound of the gunshot. Slim understands George and Lennie's relationship and consoles George. Curley and Carlson do not understand George and Lennie's relationship and wonders why George is looking depressed.