First, you need to decide on a thesis. This thesis will become the main idea for your essay. Perhaps you can write about the isolation or loneliness that is found in the novel. Also, there is a theme of idealism versus reality:
Of Mice and Men tells the story of two simple men who try to escape homelessness, economic poverty, and emotional and psychological corruption.
Another theme deals with alienation and loneliness:
Loneliness is a recurrent theme in the novel. "Guys like us," George says, "that work on the ranches, are the loneliest guys in the world. They got no family. They don't belong no place." Lennie replies: "But not us. And why. Because . . . because I got you to look after me, and you got me to look' after you, and that's why." The alternative to the companionship that George and Lennie share is loneliness.
Possible thesis: In Of Mice and Men, loneliness is heard as a desperate cry from many of the characters.
Possible thesis: In Of Mice and Men, loneliness is a thread that runs throughout the novel.
Possible thesis: In Of Mice and Men, George finds himself more lonely than ever after shooting his companion Lennie.
Possible thesis: In Of Mice and Men, Lennie frustrates George, but George needs Lennie's companionship.
After you choose a thesis, create ideas that will support the thesis. For example, if you choose the thesis about Lennie frustrating George, you may find examples that prove this while providing evidence that George needs Lennie's companionship.
George needs Lennie to keep his dream alive. George needs Lennie to need him. George needs Lennie to have a companion who is like family. With Lennie in his life, George retells the dream. This process keeps the dream alive. With Lennie in his life, George has someone who cares about him. Lennie respects George. He tries to imitate him. He sits with his hands around his knees just like George. He pulls his hat down over his eyes just like George. Lennie tries to obey George.
Without Lennie, George cancels his dream. After Lennie's death, George realizes how much Lennie meant to him. George decides that he doesn't want to buy a farm without Lennie in his life. George is a better man with Lennie in his life:
George is loyal in his friendship with Lennie, and he is also remarkably pure of heart. When George is driven to shoot Lennie after Lennie accidentally kills Curley's wife, he destroys his own dream, too. Its fulfillment is doomed by insensitive materialists. Along with the destruction of his dream, George loses the chance to become a better man.
For a list of other themes, see the link provided below. Themes such as race and racism, class conflict, friendship, loyalty and mental disability are themes addressed in the novel.