In the Mexican countryside, a scavenger named Manuel finds a spearhead wrapped in a Nazi flag at the ruins of an old church. The spearhead is later revealed as the Spear of Destiny. Manuel becomes possessed and travels to the United States.
In Los Angeles, occult detective John Constantine exorcises a Filipina girl possessed by a demon trying to break through to Earth, which should not be possible under the rules of a standing wager between God and Lucifer for mankind's souls. Constantine's driver and apprentice Chas Kramer waits in the car as Constantine doesn't think he's ready to exorcise demons. Constantine later meets with the androgynous half-angel being Gabriel. He asks Gabriel for a reprieve from his impending death from lung cancer caused by prolonged smoking. Gabriel declines, telling Constantine that he exorcises demons for selfish reasons and cannot buy his way into Heaven.
After being assaulted by another demon, Constantine goes to Papa Midnite, a reputed witch doctor who runs a club serving as neutral ground where half-breeds do not have to conceal themselves. Constantine is admitted into the club, but the bouncer tells Chas to leave as he looks under age. Midnite does not believe Constantine's claim of demons crossing over. Constantine leaves, after exchanging hostile words with half-demon Balthazar.
Elsewhere, a woman named Isabel Dodson commits suicide in a psychiatric hospital. Her twin sister, Detective Angela Dodson, refuses to believe that Isabel, a devout Roman Catholic, would kill herself. Watching security footage of Isabel's suicide, Angela hears her say Constantine's name. Angela finds Constantine and asks him to help investigate. After they are attacked by winged demons, which Constantine believes were targeting Angela, he agrees to help.
Constantine briefly transports himself to Hell through the possession of a familiar and sees Isabel damned to eternally relive her suicide. Constantine explains to Angela that he can see the true nature of the half-breeds. He committed suicide to escape his visions and his soul was sent to Hell, but he was revived by paramedics two minutes later; for the sin of taking his own life, his soul is still condemned to go to Hell once he dies. The two examine Isabel's room in the hospital and find a clue pointing to a prophecy in the Satanic Bible that Lucifer's son, Mammon, will attempt to claim Earth as his own kingdom. To do so, Mammon requires both a powerful psychic and assistance from God.
Angela tells Constantine that Isabel, a clairvoyant and a psychic, was committed by her parents. Angela had the same gift but suppressed it. At Angela's insistence, Constantine reawakens her psychic ability through a near-death experience. She immediately finds a clue pinpointing Balthazar as an accomplice to the plot; Constantine interrogates Balthazar, who reveals that Mammon has the Spear, stained with the blood of Christ—the assistance from God. Angela, now the psychic in place of Isabel, is abducted by an invisible entity.
Constantine convinces Midnite that the demons are breaking the wager's rules. With Midnite's help, Constantine finds out how the Spear emerged and Angela's location. Constantine arms himself and goes to the hospital, reluctantly bringing Chas along. The two fight their way through an army of half-demons to exorcise Angela. Chas is apparently killed by the invisible entity, which turns out to be Gabriel. Resenting God's favoritism towards humans, Gabriel plans to unleash Hell on Earth to weed out those deemed "unworthy" of God's love. Gabriel casts Constantine from the room and prepares to use the Spear to cut Mammon free from Angela.
Out of options, Constantine slits his wrists. As he bleeds out, Lucifer arrives to personally collect his soul. Constantine tells Lucifer of Mammon's plan to usurp him. Confronted by Lucifer, Gabriel threatens to 'smite' him in God's honor; however, the attack against Lucifer comes up short, revealing to both Gabriel and Lucifer that Gabriel no longer has divine protection. Lucifer proceeds to burn Gabriel's wings, making Gabriel mortal. Lucifer banishes Mammon back to Hell and grants Constantine a wish out of gratitude; Constantine asks that Isabel be released to Heaven. Lucifer complies but realizes too late that he cannot take Constantine to Hell as a consequence; by selflessly sacrificing himself, Constantine is granted entry to Heaven. Infuriated, Lucifer heals Constantine's injuries and cures him of his lung cancer, hoping he will eventually damn himself again. Angela and Constantine depart, leaving the now human Gabriel. Sometime later, Constantine, now making an effort to quit smoking, entrusts the Spear to Angela and in a post-credits scene visits Chas's grave, where Chas appears in an angelic form, revealing that he had secretly been an immortal half-breed angel the whole time and faked his death.
