- "And yet he complained that his belly was not full."
- —Game epilogue
After Ed DeLuca's helicopter is destroyed after crashing into the Clock Tower, Frank West collapses as more zombies approach from the now breached Security Room. Isabela Keyes rescues Frank from the zombie ambush and brings him back to her hideout in North Plaza.
There, she tells Frank that he has been infected by the zombie parasite. She states that their only chance is to hinder the zombification process by crafting a suppressant by using ingredients and supplies found in the mall as well as Queens. Frank has no choice but to search for the required supplies, as he only has 24 hours to stop the infection. He faces Special Forces troops, helicopter drones, and a UH-60 Blackhawk helicopter with orders to capture any survivors they come across as he gathers the necessary supplies.
While investigating the information left behind by her brother Carlito, Isabela discovers that he has already set a plan into motion long ago. By having Isabela create a similar suppressant in their laboratory, he infected fifty orphans with the zombie parasite, administered the suppressant, and allowed them to be adopted by families all over the country, essentially planting fifty zombie time bombs.
The generator in the hideout soon starts to fail, and in order for Isabela to continue her work, Frank must retrieve a generator from the clock tower in the Leisure Park. Upon approaching the clock tower, he finds the remains of Ed's helicopter, as well as a hole in the clock tower that leads to an underground tunnel beneath the mall. The tunnel is swarming with zombies, but proves to be their only way out. Isabela then asks Frank to bring her 10 adult queens so she can extract enough of the hormone for the suppressant.
After the Queens have been collected, Isabela will administer the suppresent to Frank, successfully slowing the zombificaton process. Isabela is able to develop a pheromone that repels zombies with the left over hormones from the Queens. They then set out to the Clock Tower and prepare to use the underground tunnels as an escape.
Using Isabela's pheromone to keep the swarm of zombies away from them, Frank and Isabela head into the tunnel and follow it to the end, where they find a sewage treatment plant. They find a Humvee and attempt to escape on the vehicle, but are confronted by a XML Prototype tank manned by the leader of the Special Forces operation, Brock Mason.
While Frank drives the Humvee, Isabela operates the mounted heavy machine gun on the vehicle, eventually destroying the tank's automatic system. Brock switches the tank to manual control mode and quickly rams the Humvee, causing it to tip over on its side. Isabela is knocked unconscious while Frank stumbles out.
Brock reveals that he had commanded the Santa Cabeza operation, and that his mission is to right the mistakes that humanity has proven adept at making. As he gloats, the automatic system senses a swarm of zombies approaching and swivels the cannon around, taking Brock off guard. Frank takes the opportunity to tackle him, knocking him out of the tank and engaging him in a hand-to-hand fight.
After Brock is defeated, he falls into the zombie crowd surrounding the tank and is torn apart. Isabela, having awakened during the fight, is desperately keeping the zombies away as they threaten to topple the Humvee. As zombies continue to surround the sewage treatment plant, Frank falls to his knees and screams to the skies.
An epilogue states that Frank West later managed to escape the town of Willamette with information about the situation. He released the news, causing a worldwide fervor that leads to the United States government admitting partial responsibility for the outbreak in Santa Cabeza. However, they claim that the Willamette outbreak is the work of a terrorist group (which is technically true), and they are not to be held responsible.
The people of the world soon allowed the Willamette incident to fade from their minds. Although Carlito's plan to use the orphans to infect the entire United States has not been confirmed or proven false, it remains a chilling possibility.
- When Isabela is being escorted in Overtime Mode, she cannot be equipped and has to hold hands or be carried, but she is also immune to all damage.
- All zombies have been killed in Overtime Mode, with the exception of the zombies roaming in Leisure Park and in the Maintenance Tunnels.