Harvey Pekar (PAUL GIAMATTI) is a grumpy, middle-aged man who works as a file clerk with ultra-nerd Toby Radloff (JUDAH FRIEDLANDER) for Mr. Boats (EARL BILLINGS) at a V.A. hospital, and suffers from obsessive-compulsive disorder.
After a chance meeting with illustrator Robert Crumb (JAMES URBANIAK), Harvey decides to try his hand at drawing. He isn't any good, but Crumb is impressed by his writing and soon agrees to illustrate a comic book about everyday trivial and mundane matters that's to be known as "American Splendor."
Divorced several times over, Harvey gets a letter from comic book store owner Joyce Brabner (HOPE DAVIS) about his work. The two are soon an item and quickly marry. Yet, despite having a loving wife and being famous - including appearing on Late Night with David Letterman - Harvey is still a grumpy and cantankerous sort.
When a sudden serious illness affects him, however, and a young girl, Danielle (MADYLIN SWEETEN), comes into his and Joyce's lives, Harvey gets the chance to rethink his position on himself and the world in which he lives.