This is a first-person shooter in which players assume the role of Duke Nukem, an action hero who must save Earth from invading aliens. Players use pistols, rail guns, shotguns, explosives, and Duke's bare hands to attack and kill the alien enemies.

The majority of gameplay involves destroying these enemies in frenetic gun and laser battles in order to move on to the next section. Aliens are often decapitated or dismembered when hit, sending large splashes of blood across the ground, surrounding walls, and players' screen. Some sequences depict more 'over-the-top' instances of violence: aliens getting stabbed in the head or impaled; a human soldier bursting into bloody gibs after being tossed through propeller blades.

In one sequence, players have the ability to shoot human characters that are trapped in pod-like alien webbing; bodies explode into pieces upon impact.

During the course of the game, players enter a strip-club level and view several topless dancers and receive lap dances. A couple of missions within this level require players to recover sex toys and pictures of topless women.

A few sequences strongly imply sexual acts: two women appear to perform fellatio on the central character (e.g., raising their heads from his lap)—though there is no actual depiction of the sex act; Duke moans and leans up against the wall of a bathroom stall (furnished with a hole)—it is implied that a sex act (not depicted) occurs.

The game also contains several sexual references and innuendo in the dialogue (e.g., 'I have hungry—you have big egg ro' for me, Duke,' 'If you supply the dancing, I'll supply the pole,' and 'I'll need something naughty to play with.').

Duke's comments range from jokes about colon cleansing to several one-liners about sex and female body parts. Bathroom humor includes the ability to urinate in toilets or urinals and/or pick up feces from toilets and throw it against walls. Players can use both steroid pills and beer as power-ups; when beer is consumed, the screen temporarily blurs.

The words 'f**k,' 'sh*t,' 'c*ck,' and 'a*shole' appear in dialogue and on-screen text.