Like its predecessor, Left 4 Dead is set shortly after a worldwide pandemic of an infectious disease that rapidly transforms humans into zombie-like creatures and mutated forms that demonstrate extreme aggression towards non-infected (much like the infected in 28 Days Later). Few humans are immune to the disease, still carrying the infection but showing no symptoms. The Civil Emergency and Defense Agency (CEDA) and the U.S. military create safe zones to attempt to evacuate as many American survivors as possible. Left 4 Dead 2 introduces four new survivors—Nick, Ellis, Coach, and Rochelle, who are immune to the disease and have individual back stories that are provided through character dialogue. Like the first game, the five campaigns in Left 4 Dead 2 are set across a story arc, set in the Southern United States, which starts in Savannah, Georgia, and ends in New Orleans, Louisiana. The four survivors have to fight their way through the hordes of infected, using safehouses along the way to rest and recuperate in order to reach extraction points.
After climbing to the roof of a hotel in Savannah to be rescued, the survivors find themselves abandoned by rescue helicopters, and make their way to the local mall, after hearing word of a second CEDA evacuation point there. After a brief encounter with a gun store owner, Whitaker (voiced by Dayton Callie)the survivors discover that the mall is overrun and all of the CEDA agents have either been killed or have become infected themselves. The four then use a stock car to bust out of the mall and travel towards New Orleans ("Dead Center"). On their way there, they encounter the original survivors featured in Left 4 Dead at the portside town of Rayford ("The Passing"), who allow them to cross the bridge by first filling up its generator with gasoline. Later, they find the highway completely blocked by wrecked vehicles and are forced to travel through a still-operating but abandoned amusement park, and start a huge fireworks-and-lights show used by the rock band, The Midnight Riders, in order to attract the attention of a helicopter pilot ("Dark Carnival").
After being rescued, they realize their pilot has been infected. Nick is forced to kill him, which causes the helicopter to crash into a bayou ("Swamp Fever"). They find brief shelter in a plantation mansion and make radio contact with a Cajun boat captain named Virgil who can get them to rescue, but he needs additional diesel fuel to make it to New Orleans. Amid a torrential downpour, the survivors go ashore, make their way through an abandoned sugar mill to a gas station to get fuel supplies, and return to the boat ("Hard Rain"). Virgil takes them to New Orleans where the military appears to be evacuating civilians. The group head to the extraction point, but discover that the military is actually bombing helicopter leaving the city before the bridge is destroyed by an air strike. Judging from their dialogue, the military pilots suspect that the survivors are "carriers" ("The Parish"). Although the survivors' fate after evacuation is left unexplained after the bridge finale, Chet Faliszek, the game's writer, said that the military is taking survivors to cruise ships in an attempt to escape the worldwide infection.