John Milton (Nicolas Cage) is a criminal that has broken out of Hell to kill Jonah King (Billy Burke), a cult leader that tricked Milton's daughter into joining his followers in the wake of Milton's death, only to kill her and her husband and steal their daughter - Milton's granddaughter - to be sacrificed in a Satanist ritual.



After interrogating some of King's followers, Milton discovers that the ritual will take place in Stillwater, a prison in Louisiana. He heads there, but stops by a diner, where he meets Piper (Amber Heard), a waitress that is withholding sex from her boyfriend, Frank (Todd Farmer), so he will marry her. Milton's car is damaged, so he sabotages Piper's car and follows her to fix it in exchange for a ride to her home, which is on the way to Smithfalls.



There, Piper sees Frank having sex with another woman and they get into a fight, with Frank beating her up. Milton beats him up, knocks him out and steals the keys of his car, taking Piper along with him on a ride to Smithfalls. Meanwhile, a supernatural operative of Satan, The Accountant (William Fichtner), arrives on Earth with the mission to bring Milton back to Hell. After interrogating Frank, he discovers that Milton and Piper are heading to Louisiana and tricks the police into helping him by impersonating an FBI agent.



At a shady hotel, while Milton is having sex with a waitress, and Piper is in another room, Milton is attacked by King and his men, who heard about his return. Milton is able to kill most of them, all while still having sex with the waitress. The Accountant appears with the police and chases after Milton and Piper, who are chasing after King's RV. Milton uses a gun labeled "The Godkiller" to shoot the Accountant out of the road. They then follow King to a church, which they enter, only to be ambushed by King and captured. Piper is kidnapped and Milton is left for dead, but awakens and kills King's men before pursuing his RV once again. Inside, Piper breaks free and fights King before jumping out of the RV and onto Milton's car. King then shoots them down and escapes.



Milton and Piper then meet Milton's friend Webster (David Morse), who provides them a new car. Piper discovers that Milton had to abandon his daughter to protect her from his former companions and that's why she was so easily manipulated by King. 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. Meanwhile, the Accountant discovers that Milton is trying to save his granddaughter from being sacrificed and decides to help him, because, if there's one thing he hates more than souls that escape, is innocent souls sacrificed by madmen.



Milton tells Piper that he can not guarantee her safety and that she should leave, but she assures that she's with him until the end. They then set to Smithfalls, evading the troops of Sheriff Cap (Tom Atkins) with the help of the Accountant and finally arriving at Smithfalls, where Milton slaughters King's men before they can sacrifice the child.



King eventually shoots Milton and orders one of his servants to murder the child. However, the woman, who had been caring for the baby ever since King stole it, finds herself unable to carry out the deed, allowing Milton to grab the Godkiller and shoot King, destroying his soul. The Accountant appears and retrieves the baby, that is given by Milton to Piper. She and Webster promise to take care of the toddler as Milton dies in Piper's arms.



After both Piper and Webster have left, Milton revealed to be alive (seeing that he is already dead he cannot die again) and with the Accountant and agrees to go back to Hell with him, but warns that, one day, he will escape again. The Accountant claims that he looks forward to it, insinuating that chasing him is the most fun he would ever had. They then drive off into the gates of Hell, towards the city of Dis.