Athena-1, a research space station operated by the gene manipulation corporation Energyne, meets a catastrophic end when a laboratory rat named Larry undergoes a terrifying mutation and begins creating chaos. Among the crew, only Dr. Kerry Atkins (Marley Shelton) survives. She receives a directive from the company's CEO, Claire Wyden (Malin Åkerman), to recover essential research canisters containing a dangerous pathogen. Although Dr. Atkins manages to escape in a pod during the station's implosion, it tragically disintegrates upon re-entry, claiming her life and scattering debris across the United States. One of these canisters contaminates an American crocodile in the Everglades, while another reaches a forest in Wyoming, exposing a gray wolf to the pathogen.
Meanwhile, Davis Okoye (Dwayne Johnson), a primatologist and former U.S. Army Special Forces operative, dedicates his life to protecting wildlife at a San Diego preserve. He shares a deep bond with George, a rare albino gorilla he saved from poachers. One fateful night, a canister crashes into the gorilla's habitat, leading to George's exposure to the pathogen and resulting in alarming growth and aggression.
As the situation spirals out of control, Davis receives a call from Dr. Kate Caldwell (Naomie Harris), a genetic engineer. She discloses the grave reality that the pathogen was engineered by Energyne to manipulate genes at an alarming scale. Initially inclined to advance the CRISPR project as a means for healing, she uncovered the company's nefarious intentions to utilize the technology as a biological weapon, landing her in prison after they fired her for her whistleblowing. With George escaping captivity and rampaging through the preserve, he is soon captured by a government team under the command of Agent Harvey Russell (Jeffrey Dean Morgan).
Meanwhile, Claire and her brother Brett (Jake Lacy) employ mercenaries led by Burke (Joe Manganiello) to capture the mutated wolf, Ralph. However, their efforts end in disaster as they face fatal consequences. As Claire seeks to seize Ralph while leveraging George to eliminate Kate and erase the evidence of their misdeeds, she activates a massive transmitter atop the Willis Tower, manipulating the animals engineered to respond violently to a specific frequency, thus luring them to Chicago.
The unfolding chaos reaches a peak when George reacts violently to the sound, leading to a catastrophic plane crash. Managing to escape with Kate and Russell via parachutes, Davis soon discovers that George and Ralph have set their sights on the bustling city. With the military quickly overwhelmed by the emergence of a mutated crocodile named Lizzie, the situation worsens. Desperate, Davis and Kate set out to locate a serum, hoping it can revert the animals to their original forms.
Upon reaching Energyne headquarters in the Willis Tower, they acquire a limited number of serums. However, their victory is short-lived as Claire and Brett spot them. Claire reveals the serum merely dampens the animals' aggression, rather than restoring them to their normal sizes, and she shoots Davis before he can react, though he survives. When George ascends to the top of the tower, causing further anarchy, Claire forces Davis to create a diversion while she attempts to escape with a hostage Kate.
In a twist of fate, Kate manages to slip the serum into Claire's handbag, subsequently using a push to direct Claire towards George, who devours her alive alongside the serum. The ensuing chaos leads to George and the other animals destroying the transmitter, resulting in the collapse of the tower itself. Davis and Kate narrowly escape in a damaged helicopter as the structure falls.
Now with George's true personality restored, Davis remains behind to assist him in confronting the remaining threats, while Kate races against time to prevent the military from launching a devastating MOAB (Mother of All Bombs) strike on the city. In a climactic showdown, Russell manages to retrieve vital evidence against Brett, who ultimately meets a tragic end as rubble buries him. In a masterful display, George and Davis outsmart Ralph, leading him to meet his fate at Lizzie's jaws. Davis finishes off Lizzie by piercing her eye with an iron bar, bringing the immediate threat to an end. With the city saved, George contributes to clearing away the debris, a testament to their harrowing journey.
