The film opens in outer space of a space station Athena-1 that has been experimenting on animals using CRISPR technology. The sole remaining member, Kerry Atkins, is refused entry into the escape pod by Energyne's CEO Claire Wyden until Atkins retrieves all remaining canisters. Atkins narrowly flees from the mutated rat Larry that destroyed the station and killed off her crew and within seconds of entering her escape pod and fleeing the station, she is disintegrated by the station exploding and the canisters she had fall upon earth.
We then cut to primatologist Davis Okoye, a former US Army soldier who served in Rwanda, who is now working with gorillas at the San Diego Wildlife Sanctuary - being closest to George, who is the sole albino resident of the gorilla habitat. George is capable of using sign language to communicate with humans, but also he enjoys pranking humans in spite of being cordial to them. One night, George then encounters a canister from the space station that when he opens it, it exposes him to a green pathogen. Also, a wolf in Wyoming and a crocodile in the Everglades come in contact with their own canister.
Meanwhile, Claire Wyden and her brother Brett are angrily sulking over the loss of Athena-1 and the canisters aboard that station because they planned to sell the genetic-editing technology on the market for profit but upon hearing that animals were exposed to the canisters, Claire hatches an idea to lure those animals for dissection confident that the military will slaughter those animals and they can extract the CRISPR pathogen right out of their corpses to sell on the market for profit.
George the next morning is even bigger than usual and Davis finds him badly mauled with claw marks on his chest from grizzly bears when George trespassed into the bear habitat. This is when Davis meets Kate Caldwell, a former genetic engineer who was fired from Energyne. George gets hungrier and grows bigger, then suddenly he becomes aggressive and breaks out of his cage going on a rampage through his zoo and making the human attendants flee. The police arrive quickly and aim their guns at George (while seeing guns pointed at him happens to be his Berserk Button). Davis, although he knows the situation has now spiraled out of his control, begs the police to lower their guns and let him talk George down but the police nonetheless tranquilize George and net him.
Claire sends in a group of mercenaries by helicopter to go hunt down the wolf in Wyoming. The mercenaries, led by Burke, are quickly killed off by the wolf who also proves to be able to fly like a gliding squirrel and leap high heights. The wolf eats Burke last. George is put upon a plane with sedatives being administered into his bloodstream to ensure he cannot wake up. This is when Davis and Kate meet Agent Harvey Russell, who then informs the two about the wolf who has been nicknamed "Ralph". Claire then activates an ultrasonic signal to lure in the animals into Chicago, Illinois where Claire expects the animals to be slaughtered by the military and then she may dissect the animals' corpses for the pathogen. The signal lures in Ralph who was eating and hunting tourists visiting Mt. Rushmore and the giant crocodile in Florida. The signal wakes George up and he wreaks havoc on the plane, making it crash and forcing Davis and Kate to take on parachutes to escape. Davis also takes Russell with him but George is left on the plane to crash. The FBI come into Energyne with a search warrant and order the Wydens to surrender all material that may be linked to the giant, aggressive animals but they fail to collect the RD-19 cure which Claire secretly hid from the FBI investigators.
Helicopters that followed the plane George crashed pick up Davis, Caldwell and Russell delivering them to the U.S. Army headquarters where the "shoot first, ask questions later" Colonel Blake is leading the operations against the animals. With the help of Russell, Davis and Caldwell escape the army base by physically overwhelming the guards and stealing one of Blake's medevac choppers. George and Ralph have allied with each other and run into Chicago to look for the ultrasound transmitter, prompting the Army to evacuate everyone there.
While piloting the chopper to Chicago, Davis and Caldwell see that Chicago has not yet been fully evacuated when George and Ralph come in. The U.S. Army aggravate the gorilla and wolf even more by firing missiles and bullets, causing the two animals to retaliate and advance attack causing mass casualties. With ground units failing to capture the animals, they send the Warthog after them. George and Ralph take cover and are overwhelmed until the giant crocodile Lizzie pops out of the river, flips over a boat filled with evacuating civilians and makes a huge roar. Lizzie then demolishes the army blockade and the Warthog thus allowing George and Ralph to continue on their rampage. It now becomes clear that the U.S. Army cannot kill or even hurt the three animals and Davis and Caldwell finally reach Energyne to search for the antidote RD-19. Caldwell finds the RD-19, but the Wydens show up and hold Davis and Caldwell at gunpoint forcing Caldwell to hand over the RD-19. Caldwell sneaks one into her pocket while Claire takes the rest and puts them in Brett's bag. When Davis refuses to comply to her orders, Claire shoots him and he collapses, supposedly killing him. Claire even mentions that she killed Caldwell's brother, angering Caldwell. Claire forces Caldwell to board a chopper on the helipad so that she can force Caldwell to reverse-engineer the pathogen and create an even stronger antidote. At the time, the three animals arrive and climb the Energyne HQ to seek and destroy the signal's source.
As Claire is about to get Caldwell to board the helicopter, George reaches the helipad and makes a roar (scaring away Brett who was carrying the RD-19 canisters) before George partially damages the helicopter and kills the pilot. Davis then pulls away Kate to safety, which proves that Davis survived the gunshot and he was only wounded. Kate claims she still has one RD-19 but because it can only go to one animal, Davis picks George to take it so that George may fight off the wolf and crocodile. Claire who also survived George's assault then uses her gun to force Davis and Kate to distract George since she also wants to run away from the animals. Davis calls for George and then Kate puts the RD-19 into Claire's bag then shoves Claire into George's hand, and George devours Claire (and the RD-19) while pummeling down the ultrasonic signal transmitter.
With the Energyne building collapsing, Brett attempts to run away but on the first floor he is stopped by Russell who forces him to choose either going to jail or surrender his laptop (that has evidence incriminating Claire) and his pet rat then run out an unsafe exit. Brett eagerly chooses the latter, and gets killed by falling debris. Russell and the rat escape through a safer exit. The Energyne building starts tumbling down with the three animals, Davis and Kate still on it but they survive the crash.
George reverts back to his friendly self with the RD-19 clearing his aggression, but as Claire advised, the RD-19 cannot shrink George back down to his original size which Davis decides for the moment that'll be a good thing to take down Ralph and Lizzie. The three monsters battle each other (George and Davis vs. Ralph vs. Lizzie) resulting in Lizzie killing Ralph and overpowering George. Davis attacks Lizzie with firepower but to no avail. After running out of ammo, Lizzie corners Davis before George finally kills Lizzie with a rebar into her eye. George seemingly dies from the attacks Lizzie inflicted on him, making Davis sadly accept his friend had to sacrifice himself to save the city from Lizzie and Ralph but it turns out he was just pranking with Davis.
The film ends with George helping out survivors of the battle and Davis makes plans on finding a new home that's big enough for George, accepting the idea that George is apparently stuck as a giant.
