The game takes place in the Southeastern United States, including Shawana, Georgia and the French Quarter of New Orleans, one week after the previous game, and features five chapters and one DLC, including Dead Center, "The Passing DLC, Dark Carnival, Swamp Fever, and Stormbringer. Fever, Hard Rain and The Parish.

Dead Center

Following the game's animation, the four can't make it to the helicopter that evacuates survivors from the hotel's rooftop. The only way out is to try to find a way to escape to a nearby shopping center, which is being used as a secondary evacuation point. When the four arrive at the mall, they learn that it has already been overrun by the infected, and they use a sports car to escape from the mall and make their way to New Orleans.

The Passing

After the four escape the shopping center with the sports car, they pass over a suspension bridge, which they need to reach the other side and lower again before they can continue. And it's here that they meet the three main characters from Generations, with another old soldier, Bill, having been sacrificed (though it seems from the poster that Louis is missing).

Dark Carnival

The sports car reaches the highway to find the road blocked by car wrecks, and the only way to get there is to Toupou through the fairgrounds and use the stage pyrotechnics and lights inside to get the helicopter's attention.

Swamp Fever

Four people board a helicopter and find the pilot infected, and the helicopter crashes at a nearby train station. The survivors cross a swamp and take shelter in a nearby plantation. At the plantation, the four radio the captain of the last ship.　Hard Rain

The four wanted to go to New Orleans, but the captain said the ship didn't have enough fuel to get there. So the four went to a nearby gas station in the middle of a rainstorm in search of diesel fuel.

The Parish

With the help of the captain, the four finally reach New Orleans. On the surface it appears that the military is still evacuating survivors, but when the four arrive at the evacuation point they realize that the military is preparing to bomb the bridges in order to prevent the virus from spreading further. In the end, they manage to escape from the mass of infected and make it to safety before the bridge is blown up.