The zombie infestation has spread all over the world, reducing the world into desolation with the civilization collapsing. In 2019 (16 years after the events of The House of the Dead 4), a paramilitary force led by retired AMS agent Thomas Rogan infiltrates the EFI Research Facility, a research center formerly owned by Dr. Roy Curien located in an unnamed place in Europe or North America, to investigate what led to the world's collapse. During the mission, his entire team is killed, until he and his second-in-command, Captain Dan Taylor are left. When they manage to find their answer in a giant laboratory, Death, a gigantic mutant who serves as the facility's security guard, kills Taylor and injures Rogan. While fighting to stay alive, Rogan is approached by an unidentified figure in a semi-corporate attire who offers help. Contact with him is lost. Two weeks later, on October 31, Rogan's daughter, Lisa, accompanied by his former partner, semi-retired agent "G", arrives at the facility to rescue him. While navigating through the facility, they fend off against hordes of undead creatures, before they encounter Death, whom they fight twice. Later, they fight a deformed sloth, The Fool, and a mutated tendrilous plant named The Sun. Along the way, Lisa muses to "G" how she has to live in the shadows of her well-known father and that she is often the subject of his comparison.