NOTE: This spoiler was submitted by Jeremy

The film opens in a location called “The New World”. A ship of hunters sails across desert sand. They awaken a sand-dwelling creature called a Diablos. Several hunters are lost as the beast attacks the ship. In the chaos, one lone hunter (Tony Jaa) falls from the ship and is left behind by his crew.

In our world, a team of soldiers, led by Captain Natalie Artemis (Milla Jovovich), are gathered in the desert for a mission. Artemis leads Dash (Meagan Good), Link (Tip “T.I.” Harris), Marshall (Diego Boneta), Steeler (Josh Helman), and Ax (Jin Au-Yeung) to a site where several markers are held up. Along with another team, they come across a storm that is activated by the markers. The ground begins to shake and crack open, sending Artemis and her team falling down a crevice.

The team wakes up in the desert. They come across the charred remains of the B-team, burnt by something more powerful than anything manmade. Artemis leads her team in their vehicle until they come across what appears to be a giant ribcage. From a distance, the Hunter can see them and attempts to warm them with an arrow covered in chalk, but the men misinterpret it as an attack and fire on him. Soon, the Diablos begin to make its way toward the team underground before bursting out of the sand. It chases them down as they try to fire upon it. Ax is killed when the Diablos swings at him while Steeler is impaled by its horn. They lose the beast by hiding in a cave.

When the team appears to be safe overnight, they are found by other cave-dwelling spider monsters called Nerscylla. Marshall is eaten by one just before Artemis is knocked unconscious. She awakens in a web pod made by the Nerscylla. She finds Dash dead and tries to make her way out before she is found by a barely alive Link. He starts to complain about a pain in his body, which is revealed to be a bunch of eggs formed onto his skin. As they start to hatch, the bigger Nerscylla devours Link as Artemis flees. She makes it outside the cave to find the daylight, which the Nerscylla are weakened by.

Artemis is found by the Hunter, both of them believing the other to be a threat. After they fight, the Hunter takes Artemis captive as he brings her back to his cave to avoid the Nerscylla. He denies her food and water as they hear the creatures trying to get in. Artemis eventually frees herself and continues to fight the Hunter, even tying him up herself. He kicks the water away from her, and she retaliates by throwing something at two small figures he appears attached to. Their fighting eventually leads them to attract more Nerscylla, so they compromise to a truce. Artemis even gives the Hunter some chocolate that she was carrying, which leads him to develop a taste for it. He responds by giving her water.

Artemis makes it clear to the Hunter that she needs to return home through the rift that brought her there, but she cannot do that without getting past the Diablos. The Hunter suggests that they use the Nerscylla’s venom to poison the Diablos. He then helps Artemis prepare to fight the creatures by showing her how to wield his weapons. They set a trap for one Nerscylla and take its fang before retreating to the cave. There, Artemis teaches the Hunter some of her language, while she learns that the two figures he carries represent his wife and child that he lost a while ago.

The next day, Artemis and the Hunter head out to take their stand against the Diablos. They lure it to a shipwreck and fire arrows laced with Nerscylla venom at it. Artemis fires what she can at the Diablos while the Hunter tries to drive his sword into the monster’s head. The Diablos knocks him off, but Artemis makes her way to the top of its head and jams the sword deeper into its skull until the beast is finally brought down. Artemis then goes to tend to the Hunter. She manages to revive him, and they continue on their journey.

The two make their way to an area with herbivorous monsters dwell. Further up is the Sky Tower that can get Artemis home. They gather food and water before setting up camp for the night. Later, a larger winged monster called the Rathalos begins to set the forest ablaze, frightening the other monsters and sending them running on fire. The Hunter’s previous crew, led by the Admiral (Ron Perlman), arrives to send the creatures away and get Artemis and the Hunter out of danger. However, just after Artemis thanks the Admiral, he knocks her unconscious.

Artemis wakes up chained in a cage with the other crew members observing her like an animal. They also have a Felyne (humanoid cat that’s also their chef). The Admiral frees Artemis and explains that he is just protecting his world and knows that others like Artemis have crossed over into this world. He believes that the gateway between worlds would cause catastrophe to this world as a result of our world’s influence. He tells Artemis about the Rathalos and that it is extremely dangerous, but it is weakest before it breathes fire. They plan to launch an attack against the beast to get Artemis home.

Artemis follows the Admiral and his crew as they attack the Rathalos. As the creature retaliates, Artemis runs off a ledge from the Sky Tower which sends her back to the regular world. She is found by other soldiers, but the Rathalos has also made its way through. It lays waste to the soldiers, but Artemis manages to grab a crossbow and an explosive. She times it just right before the creatures breathes fire, and she shoots it at its mouth, causing a massive explosion within it. That wasn’t enough to kill it, and it attempts to go for Artemis again until the Hunter shows up to fire explosive arrows at it, finally killing the Rathalos. The Admiral shows up to tell Artemis that another monster is coming to prepare another attack. Artemis decides to continue fighting with them and they launch another counterattack.

During the credits, Artemis is seen returning to New World with the Hunter and Admiral, all three still fighting the beast while a hooded figure observes from overhead. The Felyne then shows up to join in on the fight.

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A team of soldiers led by Captain Natalie Artemis is transported to an alternate world through a rift. This world is inhabited by monsters, including large dangerous ones like the Diablos, which dwells in the sand and emerges whenever someone disturbs its home. Artemis's whole team is killed by the Diablos, and spider monsters called Nerscylla. She is found by a lone Hunter, and while they fight at first, they agree to work together to fight the monsters and get Artemis home.

Artemis and the Hunter use Nerscylla venom to weaken the Diablos before they kill it by driving a sword into its skull. They venture further to the tower that creates the portal between worlds, and they are found by the Hunter's old crew, led by the Admiral, after a larger fire-breathing monster, the Rathalos, attacks. Artemis teams up with the crew to fight the Rathalos so that she can get home.

Artemis makes it through the portal to go home, but the Rathalos follows and kills the soldiers that find her. Artemis hits the Rathalos at its weak spot to ignite and explosion that severely damages but does not kill it. The Hunter finishes the job with explosive arrows. The Admiral then warns that more monsters will keep coming through, so Artemis decides to continue fighting with them in the other world.