In a stunning world where humans share their lives with a plethora of massive and ferocious creatures, a skilled hunter, portrayed by Tony Leung Chiu Wai, is cast adrift from his comrades following an assault on their sand-sailing vessel by the Diablos, a fearsome horned beast that prowls beneath the earth. Their mission takes them to the Sky Tower, the heart of power in this realm. Despite the brave efforts of their leader, the Admiral (played by Eric Tsang), to salvage the ship, chaos erupts, resulting in the hunter's separation.
Meanwhile, on Earth, Captain Natalie Artemis (Milla Jovovich) and her United Nations security unit—comprised of Marshall (Diego Boneta), Axe (Jin Au-Yeung), Steeler (Josh Helman), Lincoln (Tip "T.I." Harris), and Dash (Meagan Good)—embark on a daring operation to locate a lost battalion in the desert. Their journey is marked by ancient symbols, leading them to mysterious markers that, upon the arrival of a mighty storm, activate a portal that whisks them away to this new world. They discover the remnants of the missing soldiers, their bodies turned to char amid a backdrop of scorched earth and turned glass.
Upon repairing their vehicles, the team ventures deeper into the desert, encountering colossal skeletons and the ruthless Diablos. A warning shot from the hunter, watching from a distance, goes unnoticed as the savage beast strikes, claiming the lives of two squad members despite valiant efforts to fend it off.
The remaining survivors seek refuge in a cave, only to be besieged by the Nerscyllas, terrifying spiders that only venture out under the cover of darkness. After Artemis suffers from their venom, she awakens to a nightmarish scene—the bodies of her teammates either lifeless or overtaken by the monsters. Utilizing her resourcefulness, she ignites a flare, igniting her escape from the monstrous lair.
Emerging into the daylight, Artemis meets the hunter. An uneasy truce forms as they collaborate after an intense battle for survival, grasping the precariousness of their situation. As they uncover the purpose of the Sky Tower, the two realize that defeating the Diablos is crucial to pave their way across this perilous desert.
With the hunter teaching her the art of combat utilizing his unique weapons, Artemis meticulously formulates a plan to trap and take down the Diablos using its own venom. Their desperate endeavor concludes in success, but both pay a hefty price: the hunter sustains severe injuries. Resolute, she carries him across the desert, their journey leading them to a sanctuary inhabited by Apceros.
In the midst of chaos unleashed by the Rathalos, a fire-breathing wyvern, they find themselves saved by the Admiral who unveils the secrets of the Sky Tower and the ramifications of Earth discovering this realm. Artemis pledges to assist in dethroning the Rathalos so she can find her way home.
The tale escalates as they reach the Sky Tower, where a fierce battle ensues. Just as Artemis is pulled back to her world, chaos unfurls as the Rathalos follows, igniting catastrophe upon her rescue team. Summoning courage, she stall the beast long enough for the hunter to deliver the decisive blow.
Having faced ultimate choices, Artemis chooses to return to the New World instead of staying with her team, driven by the impending threat posed by monstrous invaders from beyond. Yet, the adventure is far from over. With new dangers looming, including the Gore Magala, Artemis knows their mission must shift: dismantling the Sky Tower becomes their urgent priority.
In a whimsical turn, a mid-credits scene reveals Palico (Aaron Beelner), the Admiral's endearing feline companion, arriving to aid in the conflict against the Gore Magala, while an ominous cloaked figure observes from above—foreshadowing greater threats ahead.
