- Jesse Custer: Annville's apathetic, alcoholic preacher who finds purpose in spreading the word of God after gaining supernatural abilities. He'll use these newfound abilities to deal with his town's secrets, lies, and twisted inhabitants, all while trying to bury the painful memory of his father's death and the years of violent crime that he engaged in.
- Tulip: A whip-smart firecracker of a human being, who can beat someone to smithereens with her bare hands. She's Jesse's ex-girlfriend, and although they had a vaguely hinted at falling out, it's clear there's still plenty of love there.
- Cassidy: A goofy vampire with a thick Irish accent who's hiding out from a group of vampire hunters hot on his trail. He's also tasked with keeping his vampirism a secret from the good townspeople of Annville, as well as his new BFF, Jesse.
- Arseface, aka Eugene Root (Ian Colletti): The son of Sheriff Root who's graphically disfigured after a botched suicide attempt, earning him the nickname "Arseface" (because he looks like a . . . well, you know).
- Sheriff Root (W. Earl Brown): The abrasive, stuck-in-his-ways, antagonistic leader of the police force in Annville, who will no doubt end up clashing with Jesse and his friends down the road.