The gameplay consists of a single game type, single- or multi-player, in which the player fights through waves of zombie-like monsters (or more precisely, specimens from a failed military experiment), with each wave becoming successively more difficult, moving through each area of the level, until it concludes with a battle with a super-specimen, called the Patriarch. Alex Quick, the level designer and texture artist, has stated that "there are a whole bunch of ideas on the drawing board that we can add in after launch, including the 'Story' mode from the mod, for instance."

Levels are completely non-linear and open-ended. There are no restrictions on where players can travel—that is, players can choose where to run and fight. Up to six players can team up in an online cooperative battle with the specimens. The game sessions are fully-configurable, so players can change the difficulty, number of enemy waves, or specify which creatures compose the waves. As the player progress through waves, the tougher-grade specimens are more commonly encountered. A software development kit (SDK) and level editor are included to aid in the creation of modifications and levels.

There is an array of weapons, including melee weapons, shotguns, rifles, sidearms and other weapons. Players must earn cash from killing specimens to buy these from the Trader who sells weapons, supplies, and ammo players will need to progress through each wave, who is only accessible after completing a wave. When the next wave begins, she relocates, and near the completion of a wave, a red arrow appears on screen, directing the players to the Trader's new location. Players can also drop cash for other players to collect and spend.

A feature called "ZEDtime" allows the player to see particularly gory kills, such as headshots, in slow-motion, even in multiplayer mode. It can also give the players an advantage for a brief time to carefully aim their shots.

Tactical gameplay elements exist, such as the ability to weld doors shut to direct the flow of the enemy hordes, and the gameplay encourages teamwork by giving less of an energy penalty when players heal each other, instead of themselves.

There is voice chat, and automatic, randomized voice responses from character interaction and selectable voice commands, for communicating with other players. Randomized music plays during set up and combat stages in each level. In set up, the music is generally ambient and quiet. In combat, it is louder, faster-paced heavy metal.

There is a "Perks" system, which gives the player certain strengths and/or abilities. Players have seven to choose from. These can be leveled up as they are used, improving their effectiveness. For example, the Commando perk gives the player a discount on automatic weapons, improved effectiveness with automatic weapons, faster reloading with all weapons, and grants detection of cloaked specimens in a radius around him.