The main irony in "Of Mice and Men" is Lennie's death at the end of the novel. George feels obliged to kill Lennie because of his love for him. The other ranch hands are furious with Lennie after he has accidentally killed Curley's wife. Because George doesn't want to allow the ranch workers to savagely murder his friend, he shoots Lennie out of mercy. The only one to understand this irony is Slim, who attempts to console George when he says, "You hadda, George. I swear you hadda."
Candy's dog and Lennie both die from the same pistol, and for the same reason: to spare them from pain and suffering. The irony here is the sadness the ranch workers felt for Candy when he lost his dog, in comparison to the lack of compassion they have for George, in the loss of his best friend.
All through the story, George complains about his responsibility for Lennie. He imagines what he could do if he wasn't encumbered by his friend, such as drinking whiskey and going to cat-houses. However, when Lennie dies, George becomes miserable and lonely, missing his friend, rather than feeling the release of his burden.
Near the end of the book, it becomes possible for George and Lennie to fulfill their dream of owning a farm, as a result of Candy's offer of a contribution. Throughout the story, George has been carefully saving money in order to achieve this dream. Lennie's death kills this dream and so, ironically, although George is free from his encumbrance, he is now trapped working for someone else.
Lennie is large and powerful, his robustness making him an asset as a ranch worker. However, his strength, combined with his love for soft things, is the cause of problems for Lennie, as it leads him to kill first a puppy and then Curley's wife. Ironically, although Lennie has the capacity to kill, he is a gentle-minded person, and never hurts anyone intentionally.