In 1719, amid the expansive Great Plains, a young Comanche woman named Naru, skilled in the healing arts, yearns to prove herself as a renowned hunter, much like her brother Taabe. While tracking deer, Naru observes peculiar lights dotting the sky, which she believes to be the mighty Thunderbird, signifying her readiness for the hunt. However, these lights originate from a Predator's dropship.
The story takes a darker turn when a tribe member falls prey to a lion. Naru joins the search party to rescue the injured man while Taabe takes on the role of a hunter, remaining behind to confront the beast. As they discover large, strange tracks and a skinned rattlesnake, Naru heads back with Paake and meets up with Taabe. Although they set a trap for the lion, tragedy strikes when Paake is killed. Brave yet wary, Naru confronts the lion, but a sudden distraction from the ominous sounds and lights causes her to lose consciousness.
She awakens safely at home, assisted by Taabe, who later brings the lion's carcass to the village, earning him recognition as War Chief. Yet, sensing a greater menace lurking in the woods, Naru sets out with her loyal dog, Sarii. In her quest, she stumbles into a bog pit but narrowly escapes an attack from a fierce grizzly bear. As fate would have it, the bear is slain by the Predator, providing Naru with a fleeting chance to evade danger before encountering a group of Comanche sent to find her.
The Predator—whom Naru refers to as Mupitsi, a creature from Comanche folklore—then ruthlessly ambushes the group, leading to a bloody confrontation while Naru finds herself ensnared in a foothold trap. Meanwhile, a group of French voyageurs captures her and Sarii. Their translator, Raphael Adolini, interrogates Naru regarding the Predator, having previously faced it himself. When Naru remains silent, the lead voyageurs resort to barbaric tactics, taking Taabe captive and using both siblings as bait to lure the Predator, which the Frenchmen desperately wish to capture.
In an intense clash, the Predator decimates most of the Frenchmen, allowing Naru and Taabe to escape. Naru manages to rescue Sarii from captivity and encounters a dying Raphael, who, in a desperate last effort, teaches her to wield his flintlock pistol in exchange for treatment for his severe injury. Utilizing herbal remedies to lower his body temperature and curb the bleeding, Naru soon realizes, as the Predator approaches, that its thermal vision cannot detect him due to his reduced heat signature.
In an unfortunate final encounter, Raphael's attempt to play dead leads to his shocking demise. But then, Taabe rides in to save Naru. Together, they bravely confront the Predator, only for the creature to ultimately kill Taabe. Heartbroken, Naru eludes danger and captures the surviving lead Frenchman. Using him as bait and consuming herbs to mask her own body heat, she cleverly awaits the Predator's approach. In a fierce showdown, she manages to use Raphael’s pistol to ambush it, knocking off its mask—an essential tool for its deadly spear gun.
Naru then cunningly leads the Predator into the bog, manipulating its own weapon against it. After a fierce struggle, with the Predator mired in the mud, its misplaced spear gun ultimately delivers fatal harm to itself. Naru claims victory by severing its head and ceremoniously painting her face with its glowing green blood, symbolizing her triumph. Upon her return to the village, she is hailed as the new War Chief, and she declares that it's time for her tribe to move on, embracing the future.
As the narrative comes to a close, a series of ledger art paintings illustrate the events, culminating in a haunting vision of three Predator vessels descending towards the tribe, hinting at the ongoing battle between hunter and hunted.
