In 1993, a new piece of technology called CRISPR was developed and then quickly used to develop dangerous experiments. In the present day, aboard a space station, a lab rat has been mutated with CRISPR and has wiped out the entire crew. Dr. Kerry Atkins (Marley Shelton) is the sole survivor, and she is contacting the heads at Energyne (the ones who developed the CRISPR mutagen) to help her return. Energyne's CEO Claire Wyden (Malin Akerman) orders Kerry to bring back the mutagen samples, or to not return at all. Kerry goes back for the samples, and the rat monster chases her. She makes it to the escape pod and is released as the station blows up with the rat still inside, but the damage to the pod causes it to break open, depressurize, and explode, killing Kerry. The samples themselves fly away across the country.
At an animal sanctuary in San Diego, primatologist Davis Okoye (Dwayne Johnson) leads co-workers Nelson (PJ Byrne), Connor (Jack Quaid), and Amy (Breanne Hill) to an ape enclosure. They observe an ape named Pavo who attempts to find a female ape to mate with, but Davis splits them up. Pavo is upset until Davis talks him down gently. Just then, an albino gorilla named George comes running in, which leads to Connor freaking out and upsetting Pavo, who runs after Connor until George knocks him over. George frightens Pavo until Davis talks to him as well. George turns out to be playful, and Davis considers him his best friend.
After work, Amy tries to invite Davis out for drinks, but he kindly turns her down. Nelson then approaches him and asks why he is closer to animals than he is with people. Davis says the animals just get him.
That night, the mutagen samples start to land. One lands in George's enclosure, another in the forest near a pack of wolves, and the last one in a river in Florida. A lone wolf is sprayed with the gas while a crocodile eats the whole sample, and George gets sprayed with it as well.
Davis is called in the next morning to check on George. Nelson tells him George is in the grizzly bear enclosure. They find a dead bear in there, and George hiding in fear. He has a scratch mark on his chest and indicates to Davis that the bear attacked him first. George steps out and has now grown up to nine feet tall.
News reports of the mutagen hitting the country has hit. Kate Caldwell (Naomie Harris) sees the news on TV, as does Claire Wyden and her brother Brett (Jake Lacy). Brett is freaking out over the amount of money they are losing, while Claire is satisfied that the mutagen for her "Project Rampage" experiment is successful. In order to handle what might happen next, Claire suggests they hire a private military group to fix things.
Kate goes to the animal sanctuary to try and talk to Davis about what has happened, as she claims to work for Energyne and is responsible for developing the mutagen, so she may be able to stop George from growing. When they try to go and find George, he is caged up until he starts to grow more aggressive. He eventually breaks free from the cage and runs loose on the sanctuary, terrifying all the guests. Davis runs after him just as the cops arrive. They aim their guns at George until Davis manages to talk George down. Things get worse as a chopper flies overhead and starts hitting George with tranquilizer darts until he passes out.
In Wyoming, the military group, led by Burke (Joe Manganiello), heads into the forest to recover the mutagen sample. Burke contats the Wydens and informs them that the container is empty. As the team moves deeper into the forest, they discover dead wolves sprawled out across the ground, as well as a massive paw print in the ground. They are then found and attacked by the mutated wolf - nicknamed Ralph - as he runs through the forest. The team shoots at him but their efforts are futile as Ralph picks them off one by one until only Burke remains. He calls to the chopper to shoot at Ralph, but the wolf leaps out of the trees and wrecks the chopper, causing it to crash down into the lake. Burke is then cornered by Ralph, and he attempts to take one last stand, but Ralph devours him.
A government agent named Harvey Russell (Jeffrey Dean Morgan) arrives at the sanctuary to bring George onto a plane to keep him contained from the public. Davis and Kate are taken in for questioning as well. Davis argues that having George on the plane is suicide, but Russell thinks they have everything under control. In the air, Russell reveals, after looking through Davis and Kate's records, that Kate had been fired from Energyne after attempting to steal research from the labs, for which she served 13 months in prison. This leads Davis to realize she was lying and that she can't fix George.
After learning of the wolf incident, Claire activates a radio frequency that calls to the mutated animals. Ralph and the crocodile - known as Lizzie - make their way to Chicago, where Energyne is located. George, despite being kept sedated, manages to hear the frequency as well and he starts to wake up. He goes into full rage mode and breaks the cage down. He attacks the agents as Davis tries to keep himself and Kate safe. George almost kills Russell until Davis intervenes, and George merely knocks Russell out. The plane's turbine blows out, and it starts to head down. Davis straps parachutes onto himself, Kate, and Russell, and they eject themselves from the plane as it crashes to the ground.
The three land and see that George survived the crash and is making his way to the city. Davis makes it clear that he doesn't trust Kate after what he's learned about her. She explains that while she was working for Energyne, her brother was stricken with cancer, and she hoped that CRISPR might cure him until she learned that Claire had been using CRISPR to develop dangerous weapons. Kate tried to make off with it but was caught and locked up. Davis then tells her how he found George. Poachers got his mother, and a scared young George was hiding under the poachers' truck. Davis and his team recovered him and killed the poachers as they had first shot at them. Russell awakens and is thankful to Davis for saving his life, so he decides to help him and Kate.
Davis, Kate, and Russell meet with a military team that is keeping surveillance on George and Ralph as they head into Chicago. They realize the animals are being called into the city, and that they must find a way to contain them. Russell helps Davis and Kate steal a chopper and make their way into the city.
George, Ralph, and Lizzie arrive in the city, leading to an all-out RAMPAGE. Davis and Kate arrive as the monsters start tearing the city apart. Knowing there's no way they'll be able to stop them on their own, they head to Energyne to find the antidote that can stop them. Davis lands the chopper, and they run into the building amidst the chaos. They find the lab with the antidote, but the Wydens find them first, and Brett holds them at gunpoint. Claire tells the two that the antidote won't make the animals return to normal, but it will only remove their heightened aggressions. takes the gun and shoots Davis in the abdomen before taking Kate with her.
The Wydens attempt to board their own chopper and make off with their materials and Kate, but the monsters start making their way up the tower. George makes it to the top and smashes the chopper, leading Brett to run away. Davis appears after surviving the gunshot and he saves Kate, but Claire is forcing them to help her. Instead, Davis distracts George long enough for Kate to take a vial of the antidote that she recovered and place it in Claire's bag. Kate punches Claire and shoves her into George's path so that he grabs Claire and eats her, along with the antidote. Meanwhile, Brett is almost out the door when he comes across Russell, who somehow made it quickly into the city. He orders Brett to hand over the laptop containing his research so that he can be free. Brett happily obliges and runs out the door...only to get messily splattered by a piece of falling debris.
Davis and Kate wait for the antidote to take effect as George continues to destroy, while Ralph and Lizzie make it to the top as well. Davis and Kate board the Wydens' chopper so that they can get enough air to avoid any serious damage. The monsters all cause the tower to collapse and go crashing down. Davis and Kate survive, and George emerges from the rubble, now back to his old self. However, Ralph and Lizzie are still rampaging, so Davis and George decide it's time to put an end to this. It also turns out that the military is trying to launch an airstrike to take out the monsters, so Kate joins Russell in trying to call it off.
George battles Ralph and Lizzie. He tosses Ralph around, but the wolf can fly and shoot quills, while Lizzie is the biggest of them all and is nigh indestructible. Davis tricks Ralph into gliding toward him, only for Davis to move and let Ralph fly into Lizzie's path. The croc grabs Ralph by the throat and bites his head off, swallowing it. George attempts to pound Lizzie, but she is too strong and she tosses George against a pole that impales him. Davis throws a grenade belt at Lizzie's neck and also tries using the chopper's artillery to take her down, but it barely scratches her. Lizzie goes after Davis and nearly eats him until George leaps into the air with the pole, and he rams it into Lizzie's eye and runs it through her head, finally killing her.
After seeing everything that happened, the military colonel calls off the strike. George appears weakened from his wound and apparently dies, only to reveal he was just messing with Davis. The heroes start to leave the city as they wonder where George's new home will be.
*CUT TO THE CHASE*
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An experimental mutagen developed by a company called Energyne is spread throughout parts of America, causing mutations in a gorilla (George), a wolf (Ralph), and a crocodile (Lizzie). The animals become gigantic and aggressive monsters that cause destruction and mayhem.
Primatologist Davis Okoye, who raised George after recovering him from poachers, teams up with Kate Caldwell, who previously worked with Energyne, and government agent Harvey Russell to stop the monsters from harming innocent lives. Claire Wyden, mastermind behind the mutagen and CEO of Energyne, calls the monsters to Chicago using a radio frequency, leading the monsters to tear the city apart.
Davis and Kate recover an antidote sample that they give to George by placing it with Claire and getting him to devour her. George is back to normal as far as his personality goes, but he is still enormous. This proves to be an advantage since Ralph and Lizzie are still going nuts. Davis tricks Ralph into getting his head eaten by Lizzie while George rams a pole through Lizzie's head before she can eat Davis.
The city (or what's left of it) is saved, and Davis now needs to find George a new home, but the two remain close friends.
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