[ MONSTER HUNTER ] In the real world, United States Army Captain Natalie Artemis and her United Nations security team search for a missing team of soldiers in the desert. A sudden storm pulls them into a portal to the New World where they find the burned remains of the missing soldiers and their vehicles. As the Diablos approaches them, the Hunter, who is observing the group, fires a warning signal. Impervious to bullets and grenades, the Diablos attacks and kills two members of the squad.
The survivors hide in a cave, where they are attacked by a pack of spider-like monsters called Nerscyllas. Artemis is injected with their paralyzing venom, and as the others try to save her, more Nerscyllas arrive and swarm them. Artemis wakes up in a Nerscylla lair, finding her team dead or infected with Nerscylla spawn, and escapes the lair by setting the pursuing monsters on fire. Above ground, she runs into the Hunter in his hideout, and after fighting each other, they grudgingly agree to cooperate.
Artemis learns that the portals are created by the Sky Tower, a structure located across the desert. To reach the Tower, the Hunter reveals they will need to kill the Diablos in order to cross the desert safely, due the fact that the Diablos species is highly territorial. Artemis learns how to fight using the Hunter’s unique bladed weapons and helps him set a trap for the Diablos to kill it with Nerscylla venom. The attack is successful, with Artemis delivering the finishing blow on the head of the Diablos, but the Hunter is badly wounded. Constructing a makeshift stretcher, Artemis dutifully carries him across the desert.
The pair reaches an oasis populated with herbivorous tortoise-like creatures called Apceros. When a Rathalos, a fire-breathing wyvern, flies by and causes the Apceros to stampede, Artemis and the Hunter are rescued by a group of hunters led by the Admiral. He explains that the Sky Tower was built by the first civilization to travel between worlds, using the monsters to protect it. Artemis agrees to help kill the Rathalos so she can return home safely.
In the ensuing battle, Artemis falls through the portal, returning to her world. But the portal does not close in time, allowing the Rathalos to though the portal and begins attacking the military team that was sent to recuse her. Artemis then realizes that the Rathalos has a weakness; when the Rathalos is about to breath fire, an explosive must be thrown inside its throat, Artemis then throws a flare into its mouth and just as the Rathalos can breathe its fire, this results in an explosion in its throat. The Rathalos however, still alive, closes in to kill Artemis, only for the Hunter (who followed Artemis and the Rathalos though the portal) to save her when he fires explosive arrows at the Rathalos, which is then killed.
Though she has the chance to stay, Artemis decides to go back to the New World and remain with the Hunters to protect the real world other monsters. The Admiral approaches her, just before the appearance of another flying monster; a black dragon known as Gore Magala. The Admiral notes that as long as the portal remains open, there will always be the threat that monsters will pass through to Earth. Artemis concludes that finding a way to take down the Sky Tower is now their primary objective as they prepare to fight the Gore Magala.
In a mid-credits scene, Palico, the Admiral’s anthropomorphic cat-like companion, arrives to help fight the Gore Magala, while an ominous cloaked figure observes the battle from the top of the Sky Tower.