John Milton (Nicolas Cage) is an undead criminal who has broken out of Hell and stolen Satan’s personal gun, labeled The Godkiller to kill Jonah King (Billy Burke), a cult leader who tricked Milton’s daughter into joining his followers in the wake of Milton’s death 10 years prior, only to kill her and her husband and steal their daughter (Milton’s granddaughter) to be sacrificed in a Satanist ritual. King believes that if he kills the baby, he will unleash Hell over Earth.
After interrogating and murdering some of King’s followers, Milton discovers that the ritual will take place in Stillwater, an abandoned prison in Louisiana. He heads there, but stops by a diner, where he meets Piper (Amber Heard), a waitress. Milton’s car is damaged in the pursuit, so he sabotages Piper’s car, a 1969 blue Dodge Charger R/T 440 and follows her to fix it in exchange for a ride on the way to Stillwater to find King.
Entering her room, Piper walks in on her boyfriend, Frank (Todd Farmer), having sex with another woman. Piper beats up the woman and assaults Frank, getting knocked to the ground. Milton, in a phone booth nearby, hears the commotion and comes to Piper’s aid, kicking Frank in the face as he is about to continue assaulting Piper, and punching Frank repeatedly. Milton steals his car, taking Piper along with him driving to Stillwater. Meanwhile, a supernatural operative of Satan, The Accountant (William Fichtner), arrives on Earth with the mission to bring Milton back to Hell and take the gun back. After interrogating Frank, he discovers that Milton and Piper are heading to Louisiana, and murders Frank with a bat before tricking a pair of state troopers into helping him by impersonating an FBI agent.
At a shady hotel, Milton is attacked by King and his men, who heard about his return, but he kills most of them. The Accountant appears with the police and chases after Milton and Piper, who are chasing after King’s van. Milton uses The Godkiller to shoot the Accountant out of the road. They then follow King to a church, only to find it filled with King’s followers. They are ambushed and captured. Piper is kidnapped and Milton is shot in the eye and left for dead, but he awakens and kills King’s men before pursuing the RV once again. Inside, Piper breaks free and fights King before jumping out of the RV and onto Milton’s car. King then disables the car by repeatedly shooting its engine.
Milton and Piper then meet Milton’s friend Webster (David Morse), who provides them a new car, a 1971 red Chevrolet Chevelle SS. Piper discovers that Milton is literally undead and had to abandon his daughter to protect her from his former companions, which is why she was so easily manipulated by King. Webster reveals that he died 10 years prior in a shootout, and that Webster personally carried his coffin. She also discovers that the Godkiller was stolen by Milton from Satan himself and has the power to completely destroy one’s soul, preventing it from going to either Heaven or Hell.