In Mexico, a scavenger recovers the tip of the
spear that pierced Jesus Christ from a ruined church and, after becoming possessed, takes it to Los Angeles. There, cynical occult expert
John Constantine exorcises a demon from a young girl after witnessing its attempt to come through her to Earth, something that should be impossible because of a treaty between Heaven and Hell. Suffering from terminal lung cancer, Constantine meets with the half-breed angel
Gabriel to request an extension to his life in exchange for his work deporting Hell's forces. Gabriel responds that performing good deeds for selfish reasons will not secure his way into Heaven.
Elsewhere, detective Angela Dodson is investigating the death of her twin sister Isabel who leaped from a psychiatric hospital roof. Angela refuses to believe her sister, a devout
Catholic, would commit suicide and condemn herself to Hell. Watching security footage, Angela hears Isabel say "Constantine", and seeks out his assistance. He refuses to help until he witnesses demons pursuing Angela and fends them off. He uses a ritual to see Isabel in Hell and confirms she killed herself. Constantine tells Angela that he committed suicide as a teenager because he was traumatized by seeing supernatural creatures and, though he was revived, when he dies he is condemned to Hell.
At the morgue, Constantine's friend Father Hennesy discovers a symbol on Isabel's wrist but is killed by the half-breed demon Balthazar. Constantine and Angela discover Hennesy carved the symbol into his hand for them to find. Angela also finds a clue hidden in Isabel's hospital room concerning a chapter of Hell's bible. Before being killed by Balthazar, Constantine's ally Beeman tells the pair the symbol represents the
antichrist Mammon,
Lucifer's son, and the chapter prophesies him usurping his father and conquering the Earth, using a powerful psychic and divine assistance; the psychic, Isabel, killed herself to stop Mammon. Angela reveals she possessed powers like Isabel's but repressed them to avoid being deemed insane like her sister. Constantine helps Angela reawaken her powers by inducing a
near-death experience, and she uses them to find Balthazar.
Constantine interrogates Balthazar and learns that the
blood of Christ on the spear tip is Mammon's divine assistance, and Angela has been chosen as his new host. An unseen entity destroys Balthazar and abducts Angela who becomes possessed by Mammon. With the help of
witch doctor Papa Midnite, Constantine induces visions to locate Angela at the psychiatric hospital. Alongside his driver and apprentice, Chas Kramer, Constantine arms himself and assaults the building, battling through hordes of demons to Angela. Constantine and Chas seemingly exorcise Mammon from her, but Chas is killed by the unseen force, revealed to be Gabriel. Resentful at
God's favoritism for humanity and forgiveness for even the most wicked, Gabriel intends to unleash Hell on Earth so that those who survive will become truly "worthy" of His love. Gabriel tosses Constantine away and prepares to pierce Angela with the spear tip to unleash Mammon.
Desperate, Constantine commits suicide by slitting his wrists, knowing that Lucifer will personally come to collect him. Time pauses and Constantine convinces Lucifer to intervene and stop Mammon. Gabriel ineffectually attempts to smite Lucifer, revealing God has abandoned them, and Lucifer burns away Gabriel's wings before banishing Mammon to Hell. Lucifer offers to restore Constantine to life for his assistance, but he instead asks that Isabel be sent to Heaven. Lucifer releases Isabel, but Constantine begins ascending to Heaven for his selfless sacrifice. Infuriated, Lucifer restores Constantine to life and removes his cancer, believing that, in time, he will prove he belongs in Hell. Constantine punches the now-mortal Gabriel before leaving and entrusts Angela with securing the spear tip. In a
post-credits scene, Constantine visits Chas's grave and witnesses Chas in an angelic form.