In 1997, Los Angeles is suffering from both a heat wave and a turf war between heavily-armed Colombian and Jamaican drug cartels. A Predator observes a shootout between the police and Colombians, watching as Lieutenant Mike Harrigan charges into the firefight to rescue two wounded officers and drives the Colombians back into their hideout. Before the police can pursue them, the Predator crashes through a skylight and kills the Colombians, using its advanced weaponry. Harrigan and his detectives Leona Cantrell and Danny Archuleta enter the building against orders and find the Colombians slaughtered. Harrigan pursues their leader to the roof and shoots him, catching a glimpse of the camouflaged Predator's silhouette but dismissing it as an effect of the heat. Harrigan is rebuked by his superiors for defying orders and is introduced to Special Agent Peter Keyes, leader of a federal task force purportedly investigating the cartels, and Detective Jerry Lambert, the newest member of Harrigan's team.
The Predator next kills several Jamaican cartel members who are in the act of murdering the Colombian drug lord. Despite being ordered to wait for Keyes, Harrigan and his team enter the pehnthouse apartment where they find the Jamaicans' skinned corpses suspended from the rafters. Keyes expels Harrigan's team from the scene, but Danny returns later to investigate further. He retrieves one of the Predator's speartip weapons from an air conditioning vent, but is killed by the Predator. Harrigan vows to bring down Danny's killer, believing that the perpetrator is an assassin involved in the drug war. A forensic scientist determines that the speartip weapon does not correspond to any element on the periodic table. Harrigan meets with Jamaican drug lord King Willie, a voodoo practitioner, who tells him that the killer is supernatural in nature. After Harrigan leaves, the Predator kills King Willie.
Cantrell and Lambert are intervening in a mugging on the subway when the Predator attacks them. Cantrell herds the passengers to safety while Lambert faces off against the Predator and is killed. The Predator is about to kill Cantrell as well, but releases her when its thermal vision reveals that she is pregnant. Harrigan pursues the Predator but is accosted by Keyes, who reveals that the killer is an extraterrestrial hunter that sees in infared, uses active camouflage, and has been hunting humans for sport around the world. Keyes and his team have set a trap for it in a nearby slaughterhouse, using thermally insulated suits and cryogenic weapons in an attempt to capture it for study. However, the Predator sees through the trap by using its mask to scan through various electromagnetic wavelenghths and kills the team. Harrigan intervenes, shooting the Predator several times and removing its mask.
Still alive, the Predator kills Keyes using a bladed throwing disc and escapes to the roof. Harrigan knocks it over the side and finds himself on a narrow ledge with the Predator hanging below. The Predator attempts to activate the self-destruct device on its forearm, but Harrigan uses the throwing disc to sever its forearm and destroy the device. The Predator falls through an apartment window and uses a medical kit to treat its wounds, then flees through the building. Harrigan follows it down an elevator shaft and finds its spacecraft in an underground chamber. Inside the ship, the two face off in a final duel , with Harrigan finally killing the Predator by impaling it in the chest with its own throwing disc. A number of other Predators appear, collecting their dead comrade and presenting Harrigan with an antique flintlock pistol labeled "Raphael Adolini 1715". Harrigan escapes the ship as it takes off and reaches the surface just as the remainder of Keyes' team arrives, furious that they were unable to capture the alien. Contemplating the pistol, Harrigan speculates that the creatures will eventually return.