Dead Rising focuses on the exploits of Frank West, a photojournalist, who is intent on breaking the story on why the fictional town of Willamette, Colorado has been sealed off by the National Guard. Frank is taken to Willamette by helicopter, as the roads leading to the town have been blockaded and the town itself quarantined.
Flying overhead, Frank notices what appears to be a brutal riot. He witnesses multiple murders and a gas station exploding during his flight. Approaching the Willamette mall, Frank sees a helipad and tells his pilot, Ed, to drop him off. Frank jumps onto the mall's roof and reminds the pilot to return in exactly 72 hours.
Frank meets up with Carlito Keyes, a Hispanic man who acts in a very mysterious nature. In reply to Frank's question about the events in town, Carlito replies that Frank should see it for himself, all the while chuckling to himself. Upon entering the mall, Frank finds there are creatures trying to enter the mall and he asks one of the survivors boarding up the entrance what the disturbance is.
The man proceeds to inform Frank of a zombie outbreak that has occurred across Willamette. The only thing preventing the zombies from entering the mall is a makeshift barricade, the zombies however swarm the shopping center after a hysterical woman breaks through the barricade in order to try and save her dog from the zombies. A Homeland Security officer named Brad appears at the top of the stairs shouting at everyone to retreat to the security room. Frank, Brad and a few other main characters are the only ones who make it to the room.
When Frank enters, the janitor welds the door shut. Brad then leaves the security room via the air ducts. Jessie, also of Homeland Security recognizes an old man she identifies as Dr. Barnaby in one of Frank's photos, but neither Jessie nor Brad are willing to share what they know. Soon, Frank returns to the mall through the air ducts.
He begins to encounter survivors, who need his assistance to make it safely to the security room, as well as survivors driven to madness by the zombie infestation, known as Psychopaths.
As the story unfolds, Frank and Brad have a series of violent encounters with Carlito, while Frank continues to bump into a beautiful Hispanic woman named Isabela. Frank and Brad are eventually able to locate Dr. Barnaby and bring him back to the security room, but it is still unknown why Homeland Security is particularly interested in Barnaby in the first place. After Frank is able to pacify a violent Isabela and bring her back to the security room, she reveals she is the sister of Carlito and that he is behind the zombie infestation.
She explains that Dr. Barnaby was the head of a research laboratory in the Central American city of Santa Cabeza, the hometown of Carlito and Isabela. The research facility was attempting to find methods of mass-producing cattle, but instead, Barnaby and his team discovered an insect called a "queen" that would turn the cattle into zombies with a single sting. After one of the "queens" escaped and infected the townspeople of Santa Cabeza, the US government sent a special forces team in to wipe out the entire city.
The massacre was covered up under the pretenses that it was a raid on drug-trade operations. Outraged over the use of unnecessary violence, Carlito planned and executed the release of numerous "queens" in Willamette in revenge. Once the importance of Dr. Barnaby is revealed, he suddenly turns into a zombie and attacks Jessie before he is killed. Jessie's fate for the moment is uncertain.
The zombie outbreak in Willamette is only the tip of the iceberg, however, as Isabela later explains Carlito has much bigger plans. Hidden beneath the mall are 5 bombs that when detonated will release queen larva into the atmosphere, making it possible for a worldwide zombie outbreak.
Depending on the player's actions from this point on, the ending for the game varies. As Frank, the player has the opportunity to complete or fail certain cases/scoops that will result in the player receiving 1 of 6 different endings.