The game uses a first-person perspective. Players move through large, interconnected levels, locate access cards and switches, find hidden areas, defeat alien enemies, and reach the exit. Environmental interaction includes opening doors, using devices, swimming, flying with a jetpack, and operating mounted machinery.

The campaign is divided into episodes containing multiple stages and boss encounters. Duke collects weapons, ammunition, armor, health, and temporary items such as steroids, night vision, and protective gear. A DOS multiplayer mode supports competitive matches over local network or modem connections, depending on the setup.

Explore every room and test suspicious walls, because secret areas often contain armor, ammunition, health, or powerful weapons.

Conserve explosive ammunition in confined spaces, use the environment against enemies when possible, and save protective items for hazards or boss encounters. Learn enemy attack patterns before spending scarce ammunition.