Athena-1, a research space station owned by gene manipulation company Energyne, is destroyed after a laboratory rat mutates and wreaks havoc. Dr. Kerry Atkins, the lone surviving crew member, is ordered by CEO Claire Wyden to retrieve research canisters containing a pathogen. Atkins is able to flee in the escape pod when the station implodes, but it disintegrates upon re-entry, killing her. The falling pieces leave a trail of debris across the United States, including the Everglades, where a canister is consumed by an American crocodile, and a forest in Wyoming, where a gray wolf is exposed to the pathogen.
Primatologist Davis Okoye, a former US Army Special Forces soldier and member of an anti-poaching unit, works at the San Diego Wildlife Sanctuary, a wildlife preserve. He befriends a rare albino gorilla named George, whom he saved from poachers. At night, one of the canisters crash-lands in George’s habitat and George is also exposed to the pathogen.
George grows considerably larger and more aggressive over time. Davis is contacted by Dr. Kate Caldwell, a genetic engineer, who explains that the pathogen was developed by Energyne to rewrite genes on a massive scale. She had hoped to advance CRISPRresearch as a potential cure for disease but discovered that Energyne planned to use it as a biological weapon. The company fired her and got her sent to prison for attempting to expose them. George escapes from captivity and goes on a rampage at the preserve. Davis calms him down, but George is captured by a government team led by Agent Harvey Russell and put on an airplane. Meanwhile, Claire and her brother, Brett, send a squad of mercenaries to capture the mutated wolf, Ralph, but they are all killed.
Claire, hoping to capture Ralph and use George to kill Kate so they can cover up their plans, uses a massive transmitter atop the Willis Tower to lure the animals – who have been engineered to respond aggressively to a certain sound frequency – to Chicago. George reacts violently to the sound and causes the plane to crash, though Davis, Kate, and Russell parachute to safety. George, who also survives the crash, joins Ralph as they make their way to Chicago. Davis and Kate convince Russell to help them steal a military helicopter, so they can get ahead of George.
By the time they arrive, George and Ralph are attacking the city. The military are already overwhelmed when the mutated crocodile, Lizzie, arrives and causes even more casualties. Davis and Kate make a plan to steal a counter-serum, with the hope that they can turn the mutated animals back to normal. They are able to reach Energyne headquarters at the Willis Tower and take several vials of the serum, but they are caught by Claire and Brett. Claire reveals that the serum only eliminates the animals’ aggressiveness, rather than revert them to their normal sizes. Claire shoots Davis, but he survives. When George climbs up to the top of the tower and causes chaos, Claire orders Davis to distract him while she attempts to escape with Kate held hostage at gunpoint. Kate slips a vial into Claire’s handbag and pushes her towards George, who swallows the terrorist whole along with the serum. Below, Russell takes a laptop of incriminating evidence from Brett and allows him to walk away, but Brett is crushed by falling debris as he leaves the tower. George and the other animals destroy the transmitter, causing the entire tower to topple over. Davis and Kate survive by hovering in a damaged helicopter amidst the shower of debris.
With George returned to his normal personality, Davis stays in the city to help him defeat the other two animals, while Kate rushes to prevent the military from deploying a MOAB to kill the creatures. George and Davis trick Ralph into flying into Lizzie’s jaws, which decapitates him, but George is overpowered by Lizzie and heavily wounded. As Lizzie nearly kills Davis, George pierces Lizzie’s eye with rebar, killing her. With the threat neutralized, the airstrike is aborted, and George helps in clearing the city of debris.