The film begins with a medical courier named Bryan, portrayed by Austin Abrams, making a delivery at a hospital. He faces unhelpful and rude staff, but his day takes an unexpected turn when Dr. Maria Stokes (Emily Piggford) approaches him for a last-minute drop-off that offers double the payment due to its location in Raccoon City. Eager to capitalize on the opportunity, Bryan agrees to take the job.
As he drives through treacherous icy roads under dark skies, he has a phone conversation with his girlfriend Michelle (voice of Sara Paxton), revealing their struggles with the topic of parenthood. Suddenly, in a moments’ distraction, he hits a woman (Andrea Miltnerova) who unexpectedly walks in front of his car. He quickly pulls over, finding her injured in the woods, and decides to take her to the hospital for help.
However, Bryan's trip takes a sinister turn when he is stopped by Sheriff Wilson (Johnno Wilson) for swerving on the road. He shows the sheriff the injured woman and agrees to follow him to the hospital. As they proceed, Bryan witnesses Sheriff Wilson's vehicle veer off-road and crash. When he approaches the wreck, he discovers the sheriff is dead and the woman is now missing. In a panic, he retrieves Wilson's gun just in time for the injured pedestrian to return, now transformed into an infected and menacing creature. In a flurry of chaos, Bryan fires the gun wildly, inadvertently damaging his own car before making a frantic escape toward a nearby house.
Inside the barn of the property, Bryan finds himself pursued by the owner's dog. Climbing to an upper level to evade the beast, he soon realizes that he is in a life-and-death scenario as the dog morphs into a horrifying mutant creature. After shooting it, Bryan enters the house, retrieves a rifle, and prepares for further confrontation. However, calamity strikes when the woman reappears and he’s forced to shoot her, leading to an eerie transformation where tendrils emerge from her neck and bind with her husband's body, creating a grotesque spider-like monster. Desperate for personal safety, Bryan attempts to escape using the couple’s truck, but ends up stuck, forcing him to continue his escape on foot.
As Bryan navigates through a dark tunnel cluttered with abandoned vehicles, he stumbles upon a little girl, hiding in a trailer. She reveals that her mother has bitten her foot. In a shocking turn, Bryan witnesses her transformation into a horrifying creature and has no choice but to defend himself, ultimately shooting her. Exiting the tunnel, Bryan is pursued by a monstrous hybrid that attempts to catch him until he is rescued by Maxine (Kali Reis) and Paul (Paul Walter Hauser).
Maxine and Paul escort Bryan toward Raccoon City General, since the package he carries holds a crucial serum meant to reverse the outbreak’s effects. During their journey, Maxine halts the vehicle when they spot a group of infected pursuing a woman down an alley. Tragically, she vanishes into the shadows. Bryan steps out to investigate, discovering only pieces of Maxine. In a desperate effort to find Paul, who is also in peril, Bryan witnesses the hybrid beast absorb both Maxine and Paul before he narrowly escapes into the sewers.
Within the sewers’ darkness, he encounters an obese man whose stomach erupts, releasing a swarm of infected rats. Using his gun, Bryan shoots the creatures before making his way back to the surface, where he is confronted by infected darting across the rooftops, splattering themselves on cars below. His determination pushes him closer to Raccoon City General, yet he realizes that the bite on his arm is becoming increasingly infected and spreading rapidly.
Fearing for his life and wanting to reach Michelle, Bryan records a final message for her, sharing his wish to have become parents together. Just then, he is noticed by a scientist, Carl (Zach Cherry), who instructs him to use the stairs to reach the 28th floor for assistance. Exhausted by the time he reaches the fourth floor, Bryan opts for the elevator, where he encounters "The Puker" (Shaun W. Loeser), a grotesque figure who spews acidic vomit, creating a life-threatening situation for Bryan.
Managing to outrun this menace, he makes it to the maternity ward, where horrors await him. Surrounded by blood sacs and infected beings, he confronts additional threats as a sac bursts, releasing an infected baby that he instinctively kills. Chaos ensues as more infected emerge, forcing Bryan to make a critical decision to save himself. He cleverly uses his last bullet to trigger a collapse that sends a horde of infected down upon the hybrid monster.
Finally reaching the scientists, they rush to create an antidote, but Bryan’s infection has escalated dramatically, mutating him into a monstrous figure. His body begins to take control as deadly tentacles emerge, leading to the tragic demise of the scientists around him in a desperate attempt to obtain the cure lost below. With the National Guard arriving overhead, Bryan, now fully transformed and overrun by his mutation, lets out a horrifying roar that echoes through the chaos of Raccoon City.
