The gameplay of Duke Nukem features a wide range of weapons such as pistols, pipe bombs, and rocket launchers, as well as the protagonist's foot to kick enemies. The game is highly interactive, allowing players to break or interact with objects in the environment, like pool tables and security cameras.
The game has a variety of levels, set in locations such as streets, churches, space stations, and Japanese villas, among others. Enemies include aliens, mutated humans, and police officers who have been turned into Pig Cops. Players can also access medikits to heal themselves, steroids for enhanced speed, night vision, protective boots, a hologram called the "holoduke", and a jetpack to reach higher areas.
The gameplay is action-oriented, but it also includes puzzles that need to be solved to progress or access secret areas. The game features network play through the IPX protocol for deathmatch and cooperative games.