Left 4 Dead 2 builds upon cooperatively focused gameplay and Valve's proprietary Source engine, the same game engine used in the original Left 4 Dead. Set during the aftermath of an apocalyptic pandemic, Left 4 Dead 2 focuses on four new Survivors, fighting against hordes of the Infected, who develop severe psychosis and exhibit zombie-like tendencies. The Survivors must fight their way through five campaigns, interspersed with safe houses that act as checkpoints, with the goal of escape at each campaign's finale. The gameplay is procedurally altered by the "AI Director 2.0", which monitors the players' performance and adjusts the scenario to provide a dynamic challenge. Other new features include new types of Special Infected and an arsenal of melee weapons.

Like its predecessor, Left 4 Dead 2 is a first-person shooter with a heavy emphasis on cooperative gameplay. The game presents five new campaigns, each composed of three to five smaller levels. As in the first game, each campaign is presented in menus and loading screens as a film starring the four Survivors; and features, upon completing a campaign, a faux credits screen which acts as the final scoreboard for the players and recaps certain performance statistics for the group. In every campaign, most levels involve the Survivors attempt to reach a safe zone and close the door once they are all safely inside. However, the final level in each campaign requires the Survivors to call for rescue and either survive a prolonged onslaught until rescue arrives, pass through an especially challenging gauntlet of Infected to reach an escape vehicle, or (in Dead Center and The Passing) collect and utilize fuel cans to enable their escape.