Left 4 Dead 2 takes place one week after the events of the first game and three weeks after the first infection. Instead of following the journey of Zoey, Francis, Louis and Bill from the first game, the player gets to control Coach, Rochelle, Nick or Ellis. They arrived a few minutes too late at the evacuation point and now need to fight their way through the south-eastern part of infected America to the next official evacuation point.

The core gameplay has not changed since Left 4 Dead. The player still looks through the eyes of one of the survivors and fights his way together with his three team mates through hordes and hordes of zombies. Instead of fighting mainly in the dark, most content of the five campaigns takes place both out in the open and in daylight. This also plays into the hands of a new feature: weather effects. The second part of the third campaign is even completely build around the theme of a heavy storm hitting a small town on the outskirts.

Heavy rain is not the only new enemy for the survivors. The zombie horde also grew through the addition of three new special infected called Charger (a smaller version of the tank), Jockey (he jumps onto a team mate and moves him away from the group), Spitter (spits deadly acid in front of the player's feet) and a new class of common infected: the uncommon common infected. They have the same basic attributes as normal zombies but have a special ability. The clown for example attracts a horde of zombies, while the riot police man is immune to damage from the front.

To take on new and old enemies the weaponry has been greatly expanded. Besides new rifles, pistols and shotguns, melee weapons such a a chainsaw, a guitar and a baseball bat have been introduced to the game. Also new is a laser sight that can be used to increase the accuracy of a weapon as well as two types of special ammunition. In addition the Boomer Bile is now available to launch at enemies and turn the raging horde against them.

Multiplayer once again consists of several different modes. Beside playing through the campaigns cooperatively and playing both the survivors and special infected in the Versus mode, the players can choose the Survival, Scavenge and Realism Mode. Survival pits the players against wave after wave of enemies with the only goal being to survive as long as possible. Scavenge requires the players to collect fuel canisters to fill up a generator while the other team, playing as special infected, tries to stop them. Realism Mode is a variation of coop-play for hardcore zombieslayers. The stakes are much higher there. The zombies can only be killed with a headshot, the witch has changed into a one-hit-one-kill-weapon, and a downed player is dead unless he is revived with the shock paddles. The last mode is Mutation, which has the player play a game with different rules. The rules are changed every week. The player might have to do the entire game using only M60's or play Survival combined with Versus.