After a run of bad luck, John (Steve Buscemi), a compulsive gambler, runs away from Las Vegas and toward a normal job and life. Taking a nondescript position in an auto insurance company in Albuquerque, he tries to get ahead in the straight world, amid the ever-present temptations of scratch-off lotto tickets. When his boss, Mr. Townsend (Peter Dinklage), asks John to accompany his top fraud debunker, Virgil (Romany Malco) on an investigation of a dubious car "accident" near Vegas, John sees an opportunity to get a promotion , though he's concerned about returning to the gambling game.

Before leaving he becomes involved with his eccentric co-worker Jill (Sarah Silverman), a dalliance that has the potential to become a real relationship. Soon John is on the road with Virgil, where they encounter a series of offbeat characters, including a wheelchair-bound stripper (Emmanuelle Chriqui), a nude militant (Tim Blake Nelson), a park Ranger (Jesse Garcia), and a carnival human torch (John Cho). While Virgil is the supposed leader of the investigation, it's John who begins to finally assert himself, pushing the case closer to a conclusion.

Through the journey, John's confidence builds, and he realizes that he can't escape his gambling addiction by running away from it-it will follow him wherever he goes. It's only when he returns to Vegas and his experiences there finally send him on the path to breaking free. First time writer/director Hue Rhodes' "Saint John of Las Vegas" follows the wild and funny trip a guy has to take to discover there's more than one way to hit the jackpot in life.