It is 2006, three years after the events of House of the Dead 4. Kate Green and Ryan Taylor — brother of her late mentor James — go undercover at a dinner event at Scarecrow Manor. The manager releases his army of mutant creatures on the guests without warning. As Kate and Ryan fight through the mansion, they uncover connections to the DBR Corporation's history — Dr. Roy Curien, Caleb Goldman, and a figure named Thornheart, who claims to be a descendant of the corporation's founders. The creatures they encounter include resurrected monsters from the 1998 Curien Mansion incident and a new squid-like behemoth called the Priestess. What Thornheart is trying to build, and what The Moon really is, waits at the end of a crumbling church escape.