Rev. Jesse Custer is a badass Texas preacher who loses his faith and learns that God has left heaven, forsaking His duties. After merging with a mysterious entity who gives him the power to make anyone do what he says, Jesse embarks on a perilous mission to literally find God, and hold Him responsible for His abdication.

Accompanying Jesse on his journey are his ex-girlfriend Tulip and a hard-drinking, beer-guzzling Irish vampire named Cassidy... but hot on their heels is the Saint ofhugers, an immortal hugging machine armed with a pair of supernatural Colt revolvers and the power to destroy entire armies.