- Madman Dr. Proton is determined to take over the world with his army of Techbots. Duke Nukem, the eponymous hero ventures through cities, chases Dr. Proton to his moonbase, and pursues him through time, to put an end to his mad schemes.
- The story takes place in the then future world of 1997 (which was the "near future" at the time of game release), in which Dr. Proton, a once sane scientist named Blunderwitz but now a radiation-lobotomized madman, is determined to take over the world. He plans to accomplish this by using his army of Techbots, advanced, mechanized killing machines designed for the singular goal of annihilation. The first stage of his takeover bid was Earth's largest city. All resistance and counter-attacks attempted by the military met with failure. Thus as a final resort, the CIA hires the eponymous hero and Ultimate Alien Butt-Kicker Duke Nukem to stop Dr. Proton's plans.
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