While there are two major characters who serve to drive the action forward, and about whom the novel is mostly written, I think there is only one true protagonist in this story.
George is the character who undergoes a change from his idealism and belief in a dream to the acceptance of the grim reality in which the weak are victimized by the strong. He tells the story of the ranch to Lennie over and over again to calm his friend and make him happy. He is, after all, the protector, the "parental figure" to this large, overgrown child-man. He admits to Candy that being with Lennie has changed him, as well. He once picked on Lennie for his own amusement, but grew to appreciate Lennie's innocence and purity in a fallen world. It is the ultimate "protection" that George offers Lennie at the end of the novel. The protection from a life filled with meanness and cruelty.
Curly's wife, I believe, is the antagonist in the novel. More complex than the other characters, she is portrayed as a "tart" or a "bitch" who seeks out the attention of other men while looking for her husband. It is her loneliness and unhappiness with her situation that drives her to prey upon the weakness in Lennie and exploit his innocence for her own gain. Curly is another antagonist, although he undergoes no significant change from the beginning of the novel to the end.
Curly's wife uses her looks and feminine nature to encourage the men, which sends Curly into rage. It is the possessive jealousy he feels concerning his wife that overtakes him and leads to her demise. Together, Curly and his wife are the antagonistic forces which thwart George's attempts to succeed at fulfilling his dream with Lennie.
The depression era itself is another antagonist in the novel. The hopelessness and desperation felt by many who were merely trying to survive is evident again and again. It is the time in history--the combination of economic, cultural, and geographical events--that place obstacles in the path of reaching the American Dream.
George is the protagonist. He changes in the book. The book starts with him and finishes with him. His ally is Slim. Candy is a foil character for George as is Crooks.