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On December 24, 2005, Sergeant Dennis Riley, member of the special U.S. Marine Team Red Light receives a distress call from Fort Stewart, a top secret research facility in Antarctica. The signal requests an immediate air strike on the base. The team is sent to investigate the matter, but their plane crashes in the tundra. When Dennis arrives at the facility he finds out that something horrible has occurred, and must fight for his life as he encounters mutated creatures and is in danger of getting infected himself.

Extermination is a survival horror game. The player character has limited ammunition for his firearms and in many cases it is advisable to run away from monsters. Besides the traditional health bar Dennis also has an Infection Rate, which may gradually grow when attacked by monsters. Once his Infection Rate reaches 100% he becomes very weak and would eventually mutate into a monster. Infection can be countered by applying MTS vaccines.

The player character's default weapon, a special purpose rifle, can be customized with enhancements such as zoom scope, flashlight grip, radar, and parts which convert it to other weapon types such as flame thrower, shotgun, or rocket launcher. Dennis can also fight with a knife. Throughout the game batteries must be collected and used for activating various machines and saving the game.