Athena-1, a research space station owned by gene manipulation company Energyne, is destroyed after Larry, a laboratory rat mutates and wreaks havoc. Dr. Kerry Atkins, the lone surviving crew member, is ordered to retrieve research canisters containing a pathogen by CEO Claire Wyden. Atkins is able to flee in the escape pod when the station imploded, but it disintegrates upon re-entry, killing her, and leaving 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 a San Diego 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 CRISPR research 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 is put on an airplane. Meanwhile, Claire and her brother, Brett, send a squad of mercenaries led by Burke 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 crashes the plane, though Davis, Kate, and Russell parachute to safety. George, who survived the crash, joins Ralph as they make their way to Chicago. Davis and Kate convince Russell to help them steal a military medical 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. 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. George and the other animals destroy the transmitter, causing the entire tower to topple. 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 flees to prevent the military from deploying a MOAB to kill the creatures. Russell is able to take a laptop of incriminating evidence from Brett, then allows him to walk into the path of some falling rubble, which fatally crushes him. George and Davis trick Ralph into flying into Lizzie’s jaws, which decapitates him, then 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.