Duke Nukem, working for General Graves, is asked to investigate Area 51, after reports indicate the hostile infiltration of an alien species. After getting rid of much of the alien threat there, Duke learns about how the aliens require "environmental regulators" to exist, and follows them to the Temple of Amun in Egypt.
While in Egypt, Duke Nukem discovers a vast collection of alien hybrid creatures in stasis, apparently an army meant to take over the world. A nearby power source detected by General Graves seems to supply their environmental regulators, so Duke is sent to shut it down. Subsequently, he learns that activating an override pump will drain the hibernation tanks, killing the entire alien hybrid army.
Nukem also manages to destroy the controller alien overseeing the stasis area, but it turns out that the alien activated a self-destruct sequence just before his death. Duke manages to narrowly escape the collapsing temple, using one of the alien transporters to get away.
Having re-establishing contact with the general, Duke Nukem discovers he has materialized in Sydney, Australia. Graves tells him to find one of the agency's undercover agents, who has sent out a distress call from a nearby nightclub.
After rescuing the agent, Duke locates a doomsday weapon being created by the aliens. The controller alien in Egypt had mentioned it to be able to wipe out Earth's atmosphere, so Nukem is quickly sent to destroy the device. Once successful, he transports on board the orbiting alien spaceship.
Once Duke establishes his signal with General Graves, he learns that he must hack into the spaceship's system to find a weakness. After transmitting all the data from the ship he can find, Graves tells him they have detected four human females on board which Duke must once again rescue. He finds the first one and teleports her back to Earth, and after analysis, the general learns that she is in fact a cloned version of their undercover agent, Jenny. Duke deducts that the aliens are using the clones to help propagate their species.
By the time Duke has rescued the Jennys one by one, his General friend informs him that he can destroy the ship by shutting down its engine's coolant system. He does just that, then teleports "Jenny 5" back to Earth. The General's teleportation system is unable to beam out Duke Nukem too, however, requiring him to wade through more alien assailants in order to transport out using their teleporters. The ship subsequently blows up, and Duke Nukem arrives safely back on Earth.
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