God and Lucifer have a standing wager for mankind’s souls. Angels and demons are forbidden to manifest on Earth; instead, their hybrid offspring influence humans.
In a Mexican countryside, a scavenger named Manuel finds a spearhead wrapped in a Nazi flag at the ruins of an old church, which is later revealed as the Spear of Destiny. Manuel becomes possessed and travels to the United States.
John Constantine exorcises a Filipina girl possessed by a demon trying to break through to Earth, which should not be possible under the wager’s rules. He meets with the androgynous half-angel being Gabriel. He asks Gabriel for a reprieve from his impending death from lung cancer. Gabriel declines, telling Constantine that he exorcises demons for selfish reasons and can not 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. 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 attempted suicide to escape his visions but was saved by paramedics. For the sin of attempting to take his own life, his soul is condemned to Hell. 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.