In a mysterious New World where humans share the land with a plethora of ferocious monsters, a skilled Hunter (Tony Jaa), trained specifically to track and eliminate these gigantic creatures, becomes isolated from his fellow warriors during a fierce attack on their sand-skimming ship by the Diablos, a formidable horned beast lurking underground. Their mission takes them to the Sky Tower, believed to be the heart of power in this strange realm. Luckily, the Admiral (Ron Perlman), the leader of the Hunters, manages to keep the ship afloat, but chaos ensues, and the Hunter ends up separated, landing in the treacherous sands.
Meanwhile, on Earth, a dedicated U.S. Army Ranger Captain Natalie Artemis (Milla Jovovich) leads her team—composed of Marshall (Diego Boneta), Axe (Jin Au-Yeung), Steeler (Josh Helman), Lincoln (T.I.), and Dash (Meagan Good)—on a desperate search for their lost soldiers in a vast desert. As they traverse ancient sites adorned with cryptic markings, Lincoln discovers faint tracks from their missing comrades that abruptly vanish, leaving them puzzled.
Out of nowhere, a violent storm engulfs them, triggering the ancient markers that generate a portal, pulling the crew into the New World. There, they stumble upon the charred remains of their teammates, whose demise seems to have been caused by an unknown force, as the surrounding sand has turned to glass.
As they continue their journey through this otherworldly desert, the team encounters colossal skeletons that dwarf even the largest dinosaurs on Earth. Just when they think they might be safe, the ominous Diablos returns, stalking them viciously. Quick-thinking Steeler detonates grenades in a desperate attempt to fend it off, but it barely phases the beast. In a frantic attempt to take refuge, the survivors hide within a cave, only to be besieged by nightmarish spider-like creatures known as Nerscyllas, which attack under the cover of darkness. After being injected with venom, Artemis finds herself in a lair filled with her fallen comrades, now either dead or infected.
She cleverly escapes the lair, igniting the Nerscyllas in pursuit, using a flare and some spray can to ignite a fiery disturbance. Realizing the only option is to confront the Nerscyllas during the day, she climbs to higher ground only to discover the Diablos is still lurking nearby. Just when things appear dire, she crosses paths with the Hunter, and after a tense bout of combat, they reluctantly decide to join forces to survive the night.
Guided by the Hunter's survival skills, Artemis learns the intricacies of combat with bladed weapons and devises a cunning plan to slay the Diablos using Nerscylla venom. Their collaboration pays off when they successfully deliver a fatal blow, but this victory comes at a cost, as the Hunter sustains severe injuries. With a makeshift stretcher, Artemis carries him until they discover an oasis teeming with peculiar creatures known as Apceros.
However, their moment of respite is short-lived as a fearsome Rathalos swoops down, causing a stampede among the Apceros. Just in time, they are rescued by a group led by the Admiral, who fluently communicates with them in English, revealing his background of prior journeys to Earth and the secrets of the Sky Tower—constructed by the ancient civilization to safeguard against powerful monsters.
Determined to return home, Artemis agrees to aid in bringing down the Rathalos, perceived to be vulnerable pre-attack. As they reach the precarious portal at the base of the Sky Tower, chaos erupts during an intense battle, resulting in Artemis being flung back to her world. Yet, the Rathalos breaches the portal, unleashing havoc upon the retrieval team.
In a moment of valor, she manages to slow the beast down long enough for the Hunter to deliver the lethal shot. Despite having the chance to remain back on Earth, Artemis makes the bold decision to return to the New World, standing alongside the Hunters.
The Admiral shines a hopeful light on their future, but warns that as long as the portal exists, the threat of monsters coming through remains ever-present. As they gear up to dismantle the Sky Tower and its ominous powers, the film teases further dangers with a mid-credits scene featuring Palico (Aaron Beelner), the Admiral's feline companion, preparing to confront a new enemy—the ominous Gore Magala—observed by a sinister cloaked figure at the tower's summit.
