In 2022 (a year after the zombie outbreak in Los Perdidos, California,) Frank West, a former photojournalist now working as a college professor, is approached by one of his students, Vicky “Vick” Chu, who convinces him to help her investigate a military compound, situated on the outskirts of Willamette, Colorado—the site of the first zombie outbreak. Once inside, they find out the place is being used for zombie research, but are discovered and forced to flee, with Frank labelled a fugitive after he is falsely accused by the government.
Four months later, after Christmas, Frank is found by Brad Park, an agent of the ZDC, who convinces him to help investigate a new zombie outbreak in Willamette during the Black Friday sales, in exchange for the means to clear his name and having exclusive rights to the story, revealing Vick has already left to investigate the matter herself.
Just as they arrive at Willamette, Frank and Brad’s helicopter is hit by a missile, forcing them to make a crash landing in the middle of the shopping mall. Upon confronting the zombies, they are discovered to be infected with a new, more aggressive strain of the parasite that previous treatments like Zombrex are ineffective against. Frank eventually discovers an elusive organization called “Obscuris” is in the city looking for a monstrous creature called “Calder”, and reunites with Vick on a few occasions, but their opposing views prevent them from working together.
Frank manages to approach an Obscuris truck carrying Calder, but it drives off, leaving him to confront an Obscuris lieutenant. Upon investigating the laboratory of Dr. Russell Barnaby, the main scientist behind the zombie outbreak in Santa Cabeza, Mexico, Frank learns that during his last days, Barnaby was developing ways to make zombies with their human intelligence intact. Calder was a human Obscuris soldier enhanced with a military exoskeleton transformed by accident into an intelligent but violently psychotic zombie-like mutant, who downloaded Barnaby’s data on a disk he always carries on his person. Frank finds himself having to confront Calder in order to retrieve it.
Frank later invades the base of Obscuris and faces the leader of the organization, Fontana – and the one responsible for bringing down the helicopter carrying him and Brad. Fontana reveals their group was not responsible for the outbreak. Instead they were hired by an unknown client to obtain Calder’s data, seeking to use the research on intelligent zombies to make cheap labor for factories and plantations in developing countries. Their confrontation is interrupted by Calder, who kills Fontana. After rescuing several survivors from a group of psychotic survivalists, Frank pursues Calder down to the sewers, where he steals the disk and transfers the data to his camera. Vick appears with a gun, forces Frank to give her his camera, and flees after destroying the disk. Frank runs after her all the way to the shopping mall where they are intercepted by Calder, who destroys the camera, and the two work together to kill him.
After the battle, Vick reveals to Frank she took the camera’s SD card, containing all of the disk’s data, and they reconcile, agreeing to share the credit for the story. Frank, Vick and Brad leave for the rooftop to be extracted via helicopter, but a massive horde of zombies pursue them on the way there. Brad and Vick make it to the helicopter, but Frank is grabbed as he is boarding and, unable to break free from their grip, sacrifices himself to them so Vick and Brad can escape.