Royce (Adrien Brody) awakens to find himself parachuting into an unfamiliar jungle. He meets several others who arrived in the same manner: Mexican drug cartel enforcer Cuchillo (Danny Trejo), Spetsnaz soldier Nikolai (Oleg Taktarov), Israel Defense Forces sniper Isabelle (Alice Braga), Revolutionary United Front officer Mombasa (Mahershalalhashbaz Ali), death row inmate Stans (Walton Goggins), Yakuza enforcer Hanzo (Louis Ozawa Changchien), and doctor Edwin (Topher Grace). All are armed and lethal killers, with the apparent exception of Edwin, though none know where they are or how they got there. The group follows Royce, whom Isabelle suspects is a former black operations soldier turned mercenary. In the jungle they find empty cages, plants with a neurotoxic poison that Edwin collects on a scalpel, and a deceased US Special Forces soldier. Arriving at higher ground they find themselves staring at an alien sky and realize that they are not on Earth.
The party is attacked by a pack of dog-like alien beasts, during which Cuchillo is killed. The survivors avoid a trap, as something mimicking Cuchillo's voice tries to lure them close to his slumped body. Royce guesses they are on a planet used as a game preserve, where humans are hunted as game. The group follows the quadrupeds' tracks to a hunting encampment and find a captive Predator. Three larger Predators attack, revealed to be their hunters, killing Mombasa as the rest of the group escapes. Isabelle reveals that she has heard of the Predators before, from a report by the only survivor of a Special Forces team who encountered one in Guatemala in 1987.
The group next meets Noland (Laurence Fishburne), a lone soldier who has survived on the planet for years by hiding and scavenging. He explains that the Predators sharpen their killing skills by collecting warriors and dangerous beasts from other worlds and bringing them to the planet to hunt. Noland also reveals that the Predators hunt in threes, and that there is a blood feud between the larger Predators and the smaller ones. Royce hopes that if the group can free the smaller Predator being held prisoner in the encampment, it may take them home using the other Predators' spaceship. Noland attempts to murder the group during the night, but Royce uses an explosive to attract the Predators, who kill Noland. In the ensuing chase, Nikolai sacrifices himself to kill one of the Predators using an explosive. Stans savagely attacks a second Predator with his shiv to allow the others to escape, and is killed. Hanzo duels the third Predator with a katana, killing it at the cost of his own life.
Edwin is injured by a trap as he, Royce, and Isabelle head for the encampment. When Isabelle refuses to abandon him, Royce leaves them both behind and they are caught by the remaining large Predator. Royce frees the smaller Predator and heads for the ship as the two Predators confront each other. The larger Predator kills the smaller one and then destroys the ship as it takes off. Meanwhile, Edwin paralyzes Isabelle with the neurotoxic poison on his scalpel and reveals that on Earth he was a serial killer, and feels that he fits in on this planet among the monsters. Royce appears, never having boarded the ship, and saves Isabelle by stabbing Edwin through his throat.
Royce booby-traps Edwin's body with grenades, using him as bait to disorient the Predator. A fight ensues in which Royce successfully decapitates the Predator after being saved by a sniper shot from the recovering Isabelle. As Royce and Isabelle recover from their ordeal, they observe more prey parachuting into the jungle. Royce tells Isabelle that they must find another way to get off the planet.
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