Shortly after the events of Jurassic World in 2015,^[a] a small mercenary team arrives on the abandoned Isla Nublar to collect DNA from the Indominus rex remains in the lagoon. After they collect a bone sample, the Mosasaurus devours their submersible. The Tyrannosaurus attacks their helicopter, but they manage to escape with the sample, also allowing the Mosasaurus to escape into the open ocean.

Three years later, a United States Senate committee debates whether Isla Nublar's dinosaurs should be saved from an impending volcanic eruption. Mathematician Dr. Ian Malcolm testifies that the dinosaurs should perish naturally to correct the wrongful cloning done by John Hammond. Meanwhile, Jurassic World's former operations manager, Claire Dearing, has established the Dinosaur Protection Group to save the animals. After the Senate rules against rescuing the animals, Hammond's former partner, Sir Benjamin Lockwood, summons Claire to his Northern California estate. Lockwood and his aide, Eli Mills, reveal a plan to relocate the dinosaurs to a new island sanctuary. Claire is needed to reactivate the park's tracking system to locate the animals, particularly Blue, the last surviving Velociraptor. Claire recruits Owen Grady, former Velociraptor trainer, to help capture her.

On Isla Nublar, Claire and former park technician Franklin Webb reactivate the online tracking system. Owen, paleo-veterinarian Zia Rodriguez, and a mercenary team led by Ken Wheatley, track and find Blue. The encounter escalates, resulting in Blue being shot and Wheatley tranquilizing Owen. Wheatley then abandons Owen, Claire, and Franklin on the island while forcibly taking Zia hostage to treat Blue. The ship, loaded with captured dinosaurs, departs as the remaining dinosaurs are left behind to die in the eruption. Claire, Franklin, and Owen sneak aboard the ship and help Zia transfuse Blue with Tyrannosaurus blood to save her life.

Rather than being relocated to a new island, the captured dinosaurs are transported to the Lockwood estate, where Lockwood's orphaned granddaughter, Maisie, overhears Mills and auctioneer Mr. Eversoll secretly planning to sell the dinosaurs on the black market. They will also preview the Indoraptor, a weaponized, transgenic dinosaur created by geneticist Dr. Henry Wu using Indominus rex and Velociraptor DNA. Wu needs Blue's DNA to create an enhanced Indoraptor that is obedient to commands, unaware that Blue's blood is no longer pure. After Maisie informs Lockwood about the auction, he confronts Mills, who murders him. Maisie is later revealed to have been cloned from Lockwood's deceased daughter and the reason why John Hammond ended their association.

The auctioned dinosaurs are being immediately shipped out. Franklin evades capture and frees Zia, but Owen and Claire have been apprehended. Owen incites a Stygimoloch into breaking open their cell. The two encounter Maisie, and they learn the Indoraptor is being sold despite Wu's protests that it is a prototype. Owen disrupts the auction by luring the Stygimoloch into the room. In the ensuing chaos, Wheatley tranquilizes the Indoraptor to extract a tooth as a trophy, but the hybrid, having merely feigned unconsciousness, kills Wheatley, Eversoll, and others as it escapes. It chases Owen, Claire, and Maisie throughout the mansion until Blue, released by Zia, confronts the Indoraptor. Atop a high glass roof, both animals crash through it, killing the Indoraptor and leaving Blue unharmed.