The story begins with George Milton and Lennie Small traveling together along the Salinas River in California to find work. They have work cards indicating that there are jobs available at a nearby ranch, but they decide to stop and sleep in the woods for the evening. As they walk and talk, it becomes clear that George is in charge because something is wrong with Lennie. He doesn't behave the way most grown men behave. First, he imitates George quite often. Later, George finds him petting a dead mouse in his pocket, and when George throws it into the bushes, Lennie cries. Lennie likes to pet soft things. George has to explain that it's not sanitary to carry dead animals around. Lennie surreptiously retrieves the dead mouse when George sends him to find fire wood, but George knows he grabbed it and disposes of it again.

     George and Lennie are opposites in many ways. Not only is George the brains and Lennie the braun, but their looks are dissimilar since George is small and thin while Lennie is tall and heavy. George plans ahead and makes good choices, but Lennie can't remember anything and always makes mistakes. They are, however, dressed the same in jeans and jean jackets, carrying small bindles to sleep on which hold their possessions inside.

     Clearly, George and Lennie have known each other for a long time. George mentions Lennie's Aunt Clara, who it seems used to take care of Lennie before she died. George also comments on the fact that Lennie is always getting him in trouble. Since Lennie doesn't have common sense, he does "bad things" that get them fired from their jobs. For example, George references the last town they worked in, Weed, where Lennie tried to touch a woman's dress because it was soft. The woman became upset, which caused Lennie to grab the dress in a panic, which forced George and Lennie to run and hide in an irrigation ditch the rest of the day because the men in that town assumed Lennie was trying to hurt or take advantage of the woman.

     Through their travels, they have discussed a plan for the future. This plan, which Lennie loves to hear George describe, involves purchasing a farm of their own that they can take care of and live on self-sufficiently. George tells Lennie how he would let him take care of the rabbits that they kept on the farm, which excites Lennie to no end since rabbits are incredibly soft.

     George has a feeling that Lennie might get them in trouble again, so he tells Lennie that if anything happens, Lennie should return to the spot where they are sleeping. He wants Lennie to hide in the brush until George comes to get him. He makes Lennie repeat it over to remember the instructions then they go to sleep.

     As the book begins, it is apparent that Lennie and George are basically homeless since they travel from ranch to ranch, living wherever they work. This situation makes it clear that this book takes place during the Great Depression. Lennie and George seem to be chasing their small version of the American Dream, wanting to own their own land and not have to rely on finding work all the time. Even though George is often burdened with taking care of Lennie, they appreciate the companionship that the other offers. Lennie points out that it's nice to have someone who will look out for them if necessary. The need for friendship is an important theme in the novel.