Players enter an enclosed room, sit down, and buckle up. The game makes use of two 100-inch screens, one in front of the players and another behind, as well as a five-speaker sound system, giving the impression that enemies are attacking from all directions. The seat shakes when zombies attack, and players are blasted with air whenever they take on damage. The seat automatically rotates to face the players towards whichever screen zombies are attacking from. The game also features a new addition of a life bar. As the players are hit the life bar diminishes. If the life bar is reduced to zero the game is over. There are no continues. In the end the players are judged on how compatible they are based on performance alone.
This game features a side story in The House of the Dead plotline, taking place shortly after The House of the Dead 4, with Kate Green teaming up with G to destroy the zombie infestation at its source. They fight against the zombie infestation in the city before encountering Justice for the second time, and venture through a lab before confronting Magician Type 0, who returns after having been obliterated in two previous installments.
When the Magician is defeated, a Pandora's Box appears before him, revealing clones of him. The player must destroy the Pandora's Box with a grenade before the Magician successfully brings his clones to life. If the player succeeds, the Magician is destroyed, and Kate and G go onto their next battle. Depending on the player's performance, the Mystery Man may also appear to comment that while Pandora's Box is closed, the Wheel of Fate cannot be stopped. If the players fail, the Magician succeeds in bringing his clones to life, leaving Kate and G's fates unknown and achieving the bad ending.