A few months after the events of the first film, Professor Roy Curien at the fictional Cuesta Verde University, has managed to subdue and contain a "Hyper sapiens" specimen, who is revealed to be his son, Rudy Curien. Curien experiments on another survivor, trying to determine the source of her immortality, with apparent disregard for the rotted state of Alicia's body. When Curien has created a serum that he believes will bring back the dead and grant immortality, Curien murders one of his students and injects her with the serum. She returns to life, infects Curien and breaks out of the building. A month later, the university has a full-fledged outbreak, which is confirmed by AMS reconnaissance teams. Jake Ellis, an agent for AMS, goes in search of fellow agent Alexandra "Nightingale" Morgan. He finds her on a date at a restaurant, where she must execute several infected people before she returns to base with Ellis. After being ordered to retrieve a blood sample from the originally infected specimen on campus, they are warned that missiles will level the campus at midnight, regardless of whether the agents are still present or not. She assigns a gender-mixed Special Forces team of U.S. Marines to provide them with backup. Ellis openly questions the competence of the soldiers, leading to friction between the two units. Upon arrival at CVU, the soldiers encounter zombies. One soldier panics and another becomes infected after his gun jams. When the others discover his injury, they sever his infected arm, but he turns and infects the team medic; both are executed by Ellis. The team continues forward into the university proper. They proceed to battle through the hordes of infected, splitting into two teams. Two female soldiers, Lieutenant Alison Henson and Private Maria Rodriguez, and a male soldier, Bart, investigate the dorms. They break into a female dormitory where they find the deceased naked body of a zombie. Bart attempts to pose with the corpse and is bitten by a mosquito trapped in the room. Fearing contamination but unwilling to execute Bart, who is threatening them with a handgun, Henson handcuffs Bart to a radiator and the two soldiers exit the room, falling back to the van. Meanwhile, the second team, including Ellis and Nightingale, are attacked multiple times. Eventually, every soldier escorting them is killed, including the leader of the unit, Sergeant Griffin. They fight their way to the professor's laboratory and find the original specimen still imprisoned, as well as a pair of students, Lonny and Sarah, who had survived. They enter the confinement room and extract blood from the zombie, but are forced to kill it when it breaks free. Lonny and Sarah, who had allowed them into the confinement room are overrun and torn apart by zombies, and Ellis and Nightingale escape while the zombies are feeding on the bodies. Henson and Rodriguez make it to the extraction vehicle. There, they prepare to rescue Nightingale and Ellis, but Rodriguez is bitten by a zombie who was locked in the back of the van by the soldier assigned to guard it. Henson executes Rodriguez, and the duo arrive in front of the science building as Nightingale and Ellis fight their way through a horde of zombies. Ellis and Nightingale are saved by Henson, but the blood sample vial is destroyed in the process. They are forced to turn back, with ten minutes before the military releases the missile level the campus, and fight their way back to the confinement room. They retrieve a second vial, but Henson is bitten on the ankle. She remains behind and commits suicide, as Nightingale and Ellis escape before the missile strikes the campus. Only Ellis makes it out before the missile hits, with Nightingale surrounded by zombies. Bart breaks free from the dormitory by amputating his hand and forces Ellis to hand over the vial. Bart decides to kill Ellis anyway, but Nightingale is revealed to have survived and kills Bart. His dying action is to pull the pin on a hand grenade, destroying the vial in the process. Nightingale is wounded but uncertain of whether she's infected. Ellis refuses to execute her, and the two leave together, finding that the infection has spread to the rest of the city.
Ian Jane of DVD Talk rated it 1/5 stars and wrote, "Whereas film was so bad it was almost good, this straight-to-video sequel is just flat-out bad, and unfortunately, it's flat-out dull.... House of the Dead 2 commits the ultimate celluloid sin – it's boring." Beyond Hollywood wrote, "If you were looking for a movie to show you how generic and formulaic horror moviesin America have become lately, you needn't look any further than .... indeed an improvement over Boll's original would have worked better had it stuck to camp and not taken the whole zombie thing too seriously." Bloody Disgusting rated it 3/5 stars and wrote, "Altman’s script skewers everything in its wake, poking fun at virtually anything it can gets its bloody hands on. But underneath all the pop culture banter lies an effective film, with some palpable tension and enough blood, grue and boobs to surprise even the most jaded zombie movie hater." Jon Condit of Dread Central rated it 3/5 stars and wrote that it is deserving of a chance despite its flaws. Reviewing the DVD, Steve Barton of Dread Central rated it 3/5 stars and wrote, "It's semi-blood soaked, filled with zombies, open for business, and dare I say it, it's actually not a bad visit!"
Sequel
A third film, originally titled House of the Dead 3, had been discussed since mid 2006. Mark A. Altman said: "It's a completely different approach to the material than the first two films and I doubt it will even be called House of the Dead 3." The film directed by Patrick Dinhut and starring Dean Cain, which ended up with the title Dead and Deader when premiered on Syfy in December 2006 and released straight-to-DVD in 2007. No House of the Dead references were included in the final film.
