The player controls protagonist Chuck Greene as he fights off hordes of zombies while accomplishing specific missions. The game includes several new objects that can be used to attack the zombies. Up to 7,000 zombies can be seen onscreen at the same time.
Dead Rising 2 allows players to manufacture their own custom weapons at various points in the game by collecting items and combining them together in maintenance rooms scattered across the game map. The player also has the ability to unlock "combo cards" that reveal weapons that can be combined together. Such combinations include the "Hail Mary," a hand grenade duct taped to a football, "Dynameat," a stick of dynamite duct taped to a piece of meat, the "Paddlesaw," two chainsaws duct taped to a kayak paddle, and "Spiked Bat" which is a baseball bat with nails hammered through the item.
The game is set an unspecified amount of years after the events of the original Dead Rising. The zombie parasite that originated in Santa Cabeza and caused the Willamette outbreak has spread all over the United States. This is supposedly due to Carlito's ticking time bomb plan. The game will take place in the fictional setting of Fortune City, which is modeled after the real-life city of Las Vegas, Nevada. Chuck Greene, a former national motocross champion, is somehow caught in the middle of the zombie apocalypse in Fortune City. Just like Frank West (the player-character from the original Dead Rising), Chuck will face a number of zombie hordes as well as surviving psychopaths, and surviving civilians whom he may choose to save. Among the survivors in Fortune City is Chuck's own daughter, Katey Greene, who was infected in an attack that killed her mother. Katey serves as Chuck's primary motivation for battling the undead. He tries to earn money to keep his daughter on the infection supressant "Zombex" introduced in the original Dead Rising as the synthetic Frank West was using. Inafune mentioned in an interview that part of Chuck's quest will force him to participate in the violent game show, "Terror is Reality".