The film opens in outer space where a Predator ship is being chased by another larger one. The first ship goes through a wormhole that leads it crashing toward Earth.
Down in a forest in Mexico, sniper Quinn McKenna (Boyd Holbrook) is engaging in a hostage rescue against cartel members. Just as he gets eyes on his target, the Predator ship makes its way down. Quinn manages to kill one gang member, but his attention is drawn toward the crash. He comes across some of the Predator's armor, including its cloaking device. Before Quinn finds the Predator, his teammate Dupree (Mike Dopud) finds Quinn. They then see their other teammate, Sapir (Niall Matter), fall from a tree, hanging upside down with a lot of his flesh missing. The Predator re-emerges and kills Dupree, but Quinn uses the Predator's gauntlet to shoot something that incapacitates the Predator and also slices off the top half of Sapir's body, and the falling blood makes the Predator visible in spite of its cloaking. Soon, a government team (Project Stargazer) led by Will Traeger (Sterling K. Brown) comes down to get their hands on the Predator.
After the Predator is apprehended, Quinn takes his mask, gauntlet, and other gear to send back to his son and ex-wife's home. He swallows the cloaking device for good measure.
We meet Quinn's son Rory (Jacob Tremblay), who has autism. Some kids pull a fire alarm while he is in a room of kids playing chess, and the noises give him a sensory overload. The boys who pulled the alarm find Rory in his classroom huddled anxiously, but they leave before they can do anything more to mess with him. After the alarm is turned off, Rory rearranges the chess pieces on everyone's board. When Rory gets home, he finds Quinn's package being delivered to him. His mom Emily (Yvonne Strahovski) comes home with two potential Halloween masks (a pirate and Frankenstein's monster), but Rory doesn't want to dress up because he knows the bullies will recognize and taunt him. Rory then opens the package to find the Predator's gear, and he becomes fascinated. As he turns the gear on, the larger Ultimate Predator that was chasing the Fugitive Predator gets a lock on the gear's location, and he sets off to Earth.
Quinn undergoes a psych evaluation following the disaster in Mexico, and he's then placed with other government prisoners - ex-Marine Gaylord "Nebraska" Williams (Trevante Rhodes), Tourette's-afflicted Baxley (Thomas Jane), joker Coyle (Keegan-Michael Key), religious Nettles (Augusto Aguilera), and Lynch (Alfie Allen), who is also a former Marine. The men trade jokes and insults as they meet Quinn.
Biologist Casey Bracket (Olivia Munn) is contacted by Traeger's men and is escorted to a Project Stargazer lab to see the sedated Fugitive Predator. Casey meets Peter Keyes (Jake Busey) and then Traeger, who informs her of what they have studied from the Predator, specifically that he has traces of human DNA in him. She is heavily intrigued by the Predator and his history. Just then, the other scientists get word that the Ultimate Predator's ship is heading within close proximity of the lab. The Fugitive Predator wakes up, and as the other men try to hold him down, he starts to tear into them as he breaks out and proceeds to slaughter the men. After he takes his gear back, the Fugitive Predator spots Casey as she hides, but he doesn't harm her. A badly wounded Keyes tells Casey to not let him get away.
As Fugitive Predator is breaking out, Quinn and the other men stage a diversion to get the soldiers off the bus so they can hijack it and head off to kill the alien. Casey also runs after it with a tranq gun. She hops on top of the bus and almost has a clear shot, but she misses and shoots herself in the foot. The bus's tire gets blown out, so the men are forced to escape on motorcycles, and Quinn takes Casey with him. Meanwhile, pilots are trying to shoot down Ultimate Predator's ship, but he puts up a forcefield that prevents his ship from getting hit. The Fugitive Predator then hops in another bus, kills the men inside, and rides it into town. The Ultimate Predator descends and goes hunting with his Predator Dogs.
The guys hide out in a room with Casey until she wakes up. She thinks they are there to harm her, so she grabs a nearby shotgun, only to discover it's unloaded. As she tries to leave, Quinn tells her that if she tries to go back to the lab, they will kill her because she was carrying a vial that was on the Fugitive Predator's person, leaving Casey with no choice but to stick with the guys. Quinn then figures that the Predator is heading to Emily's house to get the gear. They take the bus to her house, but she tells them that Rory is already out of the house with the mask, so they head out to find Rory.
Rory goes out trick-or-treating with the Predator mask. The bullies manage to spot and recognize him, and they start to taunt him. Rory goes to knock on a house, but he gets no answer. The man who lives there steps out from the balcony and also taunts Rory, then he throws something at the mask. It activates and triggers a blast that kills the man and blows up his house. This also causes the bullies to run off scared. The blast is spotted by Quinn and Casey, who drive back toward that direction.
Rory walks onto a field where the Predator Dogs stalk him. Before they can attack, Quinn and the other guys drive in to fight them. Quinn manages to blow one up by shooting a grenade into its mouth, and the other one is shot to death. Fugitive Predator then shows up and grabs Nettles, ordering the gang to drop their weapons. They comply, but Quinn grabs his again and shoots at it, making him release Nettles. Everyone runs into Rory's middle school to evade the Predator. It corners and grabs Quinn, just as he tries to give back one of the Predator's weapons, but Ultimate Predator shows up and pulls Fugitive Predator through the window. The humans run away as the aliens battle each other, but Ultimate Predator smashes Fugitive Predator's face and tears his skull and spine out. He then heads off to find the humans. Afterwards, Traeger and his guys find Fugitive Predator's remains, and Traeger determines that Ultimate Predator was hunting him for something he took, and that he's also after Fugitive Predator's ship and whatever is inside. Traeger believes that if they find Rory, they will find the ship.
The gang is found by Traeger, who wants to know where the gauntlet is. He interrogates Casey and tells her that the Ultimate Predator must be upgrading himself, which is why he's so much bigger than the Fugitive Predator. They came to Earth to use human DNA while they can since they know humans are endangered, and Fugitive Predator must have been carrying something that he didn't want Ultimate Predator to get his hands (or claws) on.
Other government agents go to Emily's house to find the Predator gear, but Ultimate Predator shows up and very messily skewers all the men. He then comes across a map of where the other ship is located. Rory is also seen drawing this same map.
Quinn breaks loose from the mercs who were assaulting him and he kills them. Another merc is about to execute Casey until a third, non-violent Predator Dog shows up and gives her a grenade that she stuff in the merc's backpack, causing him to blow up and letting her loose. Traeger and his goons take Rory with them to find the other ship, so Quinn and the gang follow.
Everyone arrives at the site of the other ship. Traeger uses Rory to try and open the ship, and it works. They enter, and Quinn goes in with the cloaking device to kill one of Traeger's men for taking Rory. Outside, the rest of the gang starts to slay Traeger's goons right before Quinn holds Traeger outside at gunpoint, while his own men have him surrounded. Before anything else happens, Lynch gets his arm chopped off by Ultimate Predator. Before dying, he manages to signal the other guys. Ultimate Predator goes in, kills Traeger's men, and heads into the ship. He sends out a message that is translated to saying that he wants "McKenna" as his prize since he is the next step in the evolutionary chain. He then sets off a timer to destroy the ship.
The team heads into the woods to fight Ultimate Predator. He tosses Baxley against a tree to impale him, and then he disembowels Coyle. The two men then mutually kill each other to put each other out of their misery. Traeger gets cocky and tries to kill Ultimate Predator with one of his own weapons, but it ends up blowing Traeger's own head off. Ultimate Predator then takes Rory, as he is technically the next step in the McKenna line. Quinn, Nebraska, and Nettles hop on Ultimate Predator's ship as it flies away, but he turns on the forcefield, which slices off Nettles' legs and sends him falling off the ship to his death. Nebraska sacrifices himself by throwing his body into the ship's turbines to send it crashing down. Quinn gets in the ship and saves Rory before Ultimate Predator attacks. Casey uses the cloaking device to help Quinn fight the beast. Quinn uses the gauntlet to fire an explosive at the Ultimate Predator's leg, causing it to blow him up spectacularly. Quinn then finishes him with multiple shots to the head.
In the aftermath, Quinn takes several keepsakes representing his fallen comrades, and he and Rory take a moment to memorialize the men.
Sometime later, Quinn and Rory go to a lab where they meet Dr. Yamada (Peter Shinkoda). He brings Quinn to see the Predator's cargo that Fugitive Predator was smuggling. It opens up to reveal a powerful armor that Rory says is called the Predator Killer. The armor wraps itself around one scientist and looks like it might fire upon the others, but it turns off and goes back to normal. Quinn then declares that this is his new suit.
*CUT TO THE CHASE*
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A Fugitive Predator crash lands on Earth after being pursued by a larger, upgraded Ultimate Predator. The first Predator is taken by scientists from Project Stargazer, led by Will Traeger. He brings in biologist Casey Bracket to determine that the Fugitive Predator had human DNA, right before it escapes when the Ultimate Predator's ship is detected to be heading to Earth.
Sniper Quinn McKenna is placed with a group of government captives - Nebraska, Coyle, Baxley, Nettles, and Lynch - after a failed hostage rescue in Mexico where two of Quinn's teammates were killed by the Fugitive Predator. Quinn had sent some recovered Predator gear back to his home, which is found by Quinn's son Rory. Rory unintentionally triggers the signal to alert the Predators to his whereabouts. Quinn and the gang (now joined by Casey) find Rory and save him from Predator Dogs, but just as they are found by Fugitive Predator, Ultimate Predator eviscerates the other alien as the humans get away.
The gang is found by Traeger, who has figured that the Predators are trying to evolve using human DNA, and that Fugitive Predator was carrying something on his ship that Ultimate Predator wanted. Traeger takes Rory to find the first ship, but Quinn and the others catch up to them. Ultimate Predator kills Traeger's men and destroys Fugitive Predator's ship. After a fight in the woods, Lynch, Coyle, Baxley, and Traeger are all killed.
Ultimate Predator takes Rory with him, believing the boy to be the next step in their evolution. Quinn, Nebraska, and Nettles hop on the ship to stop him, but Nettles falls to his death, and Nebraska sacrifices himself to bring the ship down. With Casey's help, Quinn defeats and kills Ultimate Predator.
It's revealed that Fugitive Predator was carrying a Preadator Killer armor that Quinn hopes to use.
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