American Buffalo is at first glance a simple play about simple men who cannot pull off a simple robbery. The drama unwinds in Don's Resale Shop, located on the South Side of Chicago. The junk shop is littered with odds and ends, many of which are objects from the Great Depression and the 1933 Chicago World's Fair. As the play begins we learn that Don Dubrow has recently sold a coin collector a buffalo-head nickel for $90. Now sensing that this customer not only deceived him but somehow affronted his sense of professional competence, Don sets his sights on stealing back the coin and what he thinks must be the man's valuable coin collection.

Don initially picks his young friend, Bob, for the job. However, as Don and Teach, his associate, orchestrate the robbery plans, Teach argues that they should cut Bob out of the deal, an arrangement on which they agree. As it turns out, the heist never happens. Soon after midnight Bob returns, not with the but a buffalo-head nickel, which, he finally confesses, he simply purchased. After learning that Bob lied about seeing the coin dealer leave his apartment earlier that day, Don seems embarrassed and angry, and the paranoid Teach explodes, viciously attacking the helpless boy and trashing the junk shop. Their collective inability to execute a simple robbery only highlights their insignificance, while the only thing they have left of genuine value – friendship – is, like the American buffalo, pushed to the brink of extinction.