In 1719, Naru, a young Comanche woman trained as a healer, dreams of becoming a great hunter like her brother, Taabe. While tracking deer with her dog Sarii, she witnesses the arrival of a “thunderbird” in the sky (in reality a spaceship dropping off a Predator), taking it as a sign that she is ready to prove herself. Taabe agrees to take her with him as he leads a search party for the mountain lion that attacked one of the tribe’s hunters. They retrieve their wounded tribe member and depart, the mountain lion having apparently been spooked off by the Predator that follows and observes the hunters while collecting the skulls of several local predatory species. Taabe however stays behind to find the mountain lion and complete the hunt.

Naru circles back and finds Taabe. She manages to trap the lion but falls and strikes her head after being distracted by a burst of light. Taabe carries her home and returns to finish off the weakened lion, a deed for which he is honored by the chieftain and the rest of the tribe. An envious Naru leaves home with Sarii in secret the next day to hunt; she comes across a herd of skinned bison, and later tries to kill a grizzly bear but quickly gets cornered by the beast due to her lack of experience. Suddenly, she watches as the bear is overpowered and killed by her stalker, fleeing in horror before running into a pack of Comanche hunters sent to find and bring her home. The creature swiftly ambushes and kills them, and Naru tries to escape before her foot gets snagged in a metal trap. The creature, seeing that she is no longer a threat, leaves.

French voyageurs, who were the ones responsible for skinning the bison of their pelts, find Naru and cage her, ordering their translator, Raphael Adolini, to question her about the creature. When she refuses to talk, the lead voyageur reveals that he has Taabe captive as well and tortures him before tying both siblings up as bait for the predator. The creature, using its advanced weaponry, kills most of the voyageurs while Taabe and Naru escape. Naru rescues Sarii from the voyageurs’ camp and stumbles across a dying Adolini, who teaches her how to use his flintlock pistol in exchange for medical treatment. Naru gives him herbs to staunch the bleeding from his wounds and inadvertently discovers that doing so also reduces a person’s body heat, making it difficult for the creature to see one’s heat signature.

The creature fails to see Adolini with its thermal vision but finds and kills him when he makes noise. Taabe comes in on horseback to rescue Naru. The siblings are able to weaken the creature before it uses its invisibility cloak to hide and sneak up on Taabe, stabbing him through the back. Naru flees into the woods and finds the surviving lead voyageur, who had previously tortured Taabe, collecting water. She knocks him out, severs his legs, and gives him an unloaded gun before eating the herbs to hide her heat signature, baiting the creature to kill the voyageur. She uses Adolini’s pistol to ambush the predator from behind as it revels in its kill, knocking the creature’s mask off and stealing it, and runs deep into the woods to prepare for a final showdown.

Using all her knowledge of the creature’s characteristics and tactics, Naru lures it into the same mud pit she had fallen into previously, then uses the creature’s mask to turn its own projectile weapon against it. The creature dies of its wounds, and Naru severs its head and paints her face with its glowing blood. She brings the head and the flintlock pistol (revealed by the engraving to be the gun that will be handed to police officer Mike Harrigan by a Predator leader in 1997) back to her tribe, who believed her to be dead, and tells them that with the arrival of white men, it is time for them to find a new home. The tribe honors her victory as Naru, beaming with pride, turns to face a young girl. After the credits, clouds roll in and three Predator ships fly in.