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After the events of the ending first Dino Crisis, the dimensional shift damages the ecological cycle of the Cretaceous Period, threatening to erase humanity from existence. To avoid this fate, the US Senate approves the "Noah's Ark Plan" whereby the experimental Third Energy is used to send the displaced dinosaurs three million years into the future, where they would no longer be a threat; they would then be sent back to their appropriate times once the crisis passed.

The game focuses on the central character USAAF Pilot First Lieutenant Mike Wired, who is caught in an intense dogfight while defending a convoy over the Atlantic in 1943. Forced to bailout of his plane, he is fired at by an enemy aircraft while falling. Seemingly doomed to be killed, time around him freezes and he is thereafter teleported into the sky some three million years in the future, where he must fight off a murder of Pterosaurs.

When he makes it to the main land, he sees more dinosaurs and must battle them single-handedly with whatever weapons he can acquire. He hears a voice on his new wrist communicator, telling him to find a girl called Paula. When he does find Paula, she simply replies with "Trinity" before more dinosaurs appear. Trinity is actually a dinosaur with significant intelligence and it can send other dinosaurs to attack the player, as it does during a boss fight.

Eventually, Mike sees Paula is trapped in a ravine and is able to save her. After, they escape in a jeep through an empty town,

Having finally escaped from the Tyrannosaurus, the Jeep crashes near a futuristic construct, which Paula seems drawn to. The "Trinity" ambushes the pair, however, and Mike is forced to take it out before proceeding. Within the construct, a holograph of Dylan Morton, the protagonist of Dino Crisis 2 and Paula's father, appears in the centre. He explains to Mike the bizarre things that have been going on - he is in "hyperspace", a nexus of temporally-displaced lifeforms and objects (from the Mesozoic dinosaurs to the modern-day Statue of Liberty) created by the malfunctioning MTHR computer system based within a nearby volcano. The computer system must be reconfigured manually before it causes a temporal-catastrophe. Dylan also explains why Mike was chosen for the mission; he didn't want to abduct someone who could die long before they should have - as Mike was destined to be killed by the fighter in 1943, it did not matter if he was killed fighting the dinosaurs.

Mike and Paula reach the MTHR system atop of the volcano, only for the black Tyrannosaurus to return. Fighting next to lava, the Tyrannosaurus is eventually defeated, falling into the lake. With no time left Paula hesitantly reconfigures the computer system, sending her and the machine back into the future, and Mike to certain death in 1943.

Back in 1943, Mike bails out of his damaged aircraft as in the beginning of the game. With the enemy fighter's rounds about to pierce his body, they disappear one-by-one; it is revealed that Paula is using the MTHR system to displace the ammunition, thereby saving Mike. Escaping the enemy aircraft, Mike's parachute deploys as he watches his wingman down the fighter. Still remembering the whole incident, Mike thanks Paula as he lands in the water.