It's a great story about friendship, loyalty and sacrifice, but also about the struggle of the working men in the USA during the great depression. The obvious main antagonist of this story is the material conditions the characters find themselves under. Besides Curley, who's a victim of his own hubris, everyone is an almost total victim of their circumstances. The story is such blatant critique of capitalist society that I'm pretty sure it must have gotten the author on at least a few lists at the time.

It made me feel uneasy how utterly helpless most everyone in the story is. Destitute farm workers slaving away their whole life, alienated from the products of their labour, deprived of any form of community and of the prospect of ever having a family, loitering around between odd jobs, and spending every penny they make on booze and whores, the only luxury they can ever afford; a crippled black stable worker spending his life laying low and trying not to get lynched; a lonely wife of an ill-tempered failson; a mentally challenged man who is entirely dependent on his only friend and caretaker; and finally a man who sacrificed all of his life prospects to take care of him. In the end, he effectively trades his sanity to spare his friend the pain he didn't deserve.

Everyone is a loser, with the biggest one being the best man among them.