Former NYPD Captain Dewey Wilson is brought back to the force and assigned to solve a bizarre string of violent murders after high-profile magnate Christopher Van der Veer, his wife and his bodyguard are slain in Battery Park. Executive Security, the private firm employed by Van der Veer, blames the murders on terrorists, but knowing that the victim’s bodyguard was a 300-pound Haitian with voodoo ties makes Wilson skeptical. With pressure to solve the case coming from both the Police Commissioner and the Mayor, Wilson is partnered with criminal psychologist Rebecca Neff.
Elsewhere, in the South Bronx, a homeless man explores an abandoned church that is scheduled to be demolished by Van der Veer’s development company. He is killed by an unseen monstrous being. Wilson and Neff investigate his murder. At the church, apparent sounds of a baby crying lure Neff up to the bell tower. Wilson follows her but does not hear the crying; once Neff is separated from him, he hears a wolf howl. He goes up after Neff and drags her to safety. Later that night, a bridge worker is apparently murdered by the same creature.
Coroner Whittington discovers non-human hairs on several victims and consults a zoologist named Ferguson, who identifies the hairs as belonging to an unknown subspecies of Canis lupus. Ferguson compares wolves to Native Americans. Inspired, Wilson finds Eddie Holt, a militant Native activist he arrested some years previously, working in construction. While Wilson interrogates Holt on top of the Manhattan Bridge, Holt claims to be a shapeshifter, which implicates him as the killer. Wilson opts to leave Holt alone and tail him that night.
Following animal clues, Ferguson goes to Central Park, where the killer ambushes him in a tunnel. Wilson spends the remainder of his night with Neff where they have sex. The following morning, a man in a jogging suit rides Ferguson’s motorcycle past Wilson as he leaves Neff’s apartment. Whittington and Wilson stake out the church, armed with sniper rifles and sound equipment; after Whittington almost blows his ears out by opening a beer can near a parabolic microphone, an animal that appears to be a wolf kills him. Meanwhile, Executive Security apprehends a “Götterdämmerung” terrorist cell in connection with the Van der Veer slaying.
A traumatized Wilson escapes the church and finds himself at the nearby Wigwam Bar, where Holt and his friends are drinking. The group of Natives reveal the true nature of the killer as “Wolfen”, the wolf spirit. They explain that the Wolfen have extraordinary abilities and “might be gods”. Holt tells Wilson that he cannot fight the Wolfen, stating: “You don’t have the eyes of the hunter, you have the eyes of the dead”. The leader of the group, the Old Indian, informs Wilson that Wolfen kill to protect their hunting ground. Wilson resolves to end his involvement in the Van der Veer case but he, Neff and Wilson’s superior, Warren, are cornered on Wall Street by the Wolfen pack. Warren is decapitated while Wilson and Neff flee.
Wilson and Neff are cornered in Van der Veer’s penthouse by the pack, led by its white alpha male. Wilson smashes the model of the construction project that threatened their hunting ground, trying to communicate that the threat no longer exists and that he and Neff are not enemies. The Wolfen vanish just as the police barge in. Wilson claims the attack was made by terrorists. In a voiceover, Wilson explains that Wolfen will continue preying on weak and isolated members of the human herd as humans do to each other through class conflict. Wolfen will continue being invisible to humanity because of their nature; not that of spirits but predators, who are higher on the food chain than humans. The last scene is Eddie and his friends looking at the city from the bridge.