Duke Nukem Mobile is a first-person shooter that consists of 21 original levels built using assets from the original Duke Nukem 3D. The locations includes streets, the strip club, the cemetery, mansions and other locations recognizable from the game. Levels are short and square in design. In each level Duke Nukem needs to take out all enemies until one of them drops a key card. The key card is then used to exit the level. The regular arsenal of weapons and opponents is available. The four buttons to the right of the device are used to shoot, change weapon, kick, and jump.

The mobile phone versions are identical, but have upgraded graphics such as polygonal enemies.

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