The game takes place about twelve years after the events of Duke Nukem 3D. Duke is now a worldwide icon, and has achieved great fame from his heroic deeds. After sampling a video game based on his past heroics (the game Duke plays is a revamped version of the final level of the third episode of Duke Nukem 3D), he arrives on the set of a talk show for an interview. On his way to the show, Duke witnesses a news broadcast on a nearby television screen announcing that aliens have once again invaded. Unlike previous encounters, the aliens initially appear peaceful and at first seem to pose no harm to the humans of Earth. Duke's talk show appearance is cancelled to allow television stations to cover the alien invasion, and he retires to the "Duke Cave".
There, he receives a call from The President and General Graves of the Earth Defense Force (EDF). The president orders him not to harm the invaders, and adds that he is in diplomatic talks with the alien overlord. Duke obliges this request, but remains uneasy about the whole situation. However, before he can leave his chambers, he is attacked by hostile aliens. Duke is forced to disobey the president's orders and fight his way through the alien hordes in an effort to save Earth. Whilst fighting through his casino, Duke witnesses the aliens abducting women including his two live-in pop star girlfriends. Graves tells Duke that the women are being held in the Duke Dome, and that the aliens have a vendetta to settle with Duke. He also warns Duke that the aliens are using the Hoover Dam to power a wormhole so more aliens can come through. Nukem travels to the Duke Dome, using a wrecking ball to damage the building to gain access. Inside, he finds swarms of Octabrains and the missing women, who have been impregnated with alien spawn; Duke's girlfriends die after giving "birth" to alien babies. Duke finds the Alien Queen in control of the Dome and kills her, but is wounded in the process and blacks out.
After regaining consciousness, Duke fights Pigcops and aliens in through the Duke Burger. Soon he travels to the Hoover Dam in his monster truck; after battling through the dam, he finds his old friend Dylan, mortally wounded. He tells Duke that the Cycloid Emperor is at the dam, and that the only way to shut down the portal is to completely destroy the dam. Before dying, he gives Duke his demolition charges and wishes him luck. Duke places the explosives and destroys the dam, but the currents nearly drown him. Duke is revived after an EDF soldier performs CPR on him; he awakens to find the portal gone. The President, who was also at the dam, rages at Duke for ruining his plans to work with the Cycloid Emperor and that he has ordered a nuclear strike at the site of the dam to wipe out the remaining aliens, intending to leave Duke there to die. However, the Cycloid Emperor emerges and kills the President and his security detail. Duke kills the Cycloid Emperor and is rescued by Graves just as the nuclear bomb explodes.
The game ends with a satellite surveying the detonation area and listing Duke Nukem as killed in action, to which Duke replies off-screen "What kind of shit ending is that? I ain't dead, I'm coming back for more!". A short scene after the ending credits depicts a press conference, where Duke announces his intent to run for the 69th President of the United States.
There, he receives a call from The President and General Graves of the Earth Defense Force (EDF). The president orders him not to harm the invaders, and adds that he is in diplomatic talks with the alien overlord. Duke obliges this request, but remains uneasy about the whole situation. However, before he can leave his chambers, he is attacked by hostile aliens. Duke is forced to disobey the president's orders and fight his way through the alien hordes in an effort to save Earth. Whilst fighting through his casino, Duke witnesses the aliens abducting women including his two live-in pop star girlfriends. Graves tells Duke that the women are being held in the Duke Dome, and that the aliens have a vendetta to settle with Duke. He also warns Duke that the aliens are using the Hoover Dam to power a wormhole so more aliens can come through. Nukem travels to the Duke Dome, using a wrecking ball to damage the building to gain access. Inside, he finds swarms of Octabrains and the missing women, who have been impregnated with alien spawn; Duke's girlfriends die after giving "birth" to alien babies. Duke finds the Alien Queen in control of the Dome and kills her, but is wounded in the process and blacks out.
After regaining consciousness, Duke fights Pigcops and aliens in through the Duke Burger. Soon he travels to the Hoover Dam in his monster truck; after battling through the dam, he finds his old friend Dylan, mortally wounded. He tells Duke that the Cycloid Emperor is at the dam, and that the only way to shut down the portal is to completely destroy the dam. Before dying, he gives Duke his demolition charges and wishes him luck. Duke places the explosives and destroys the dam, but the currents nearly drown him. Duke is revived after an EDF soldier performs CPR on him; he awakens to find the portal gone. The President, who was also at the dam, rages at Duke for ruining his plans to work with the Cycloid Emperor and that he has ordered a nuclear strike at the site of the dam to wipe out the remaining aliens, intending to leave Duke there to die. However, the Cycloid Emperor emerges and kills the President and his security detail. Duke kills the Cycloid Emperor and is rescued by Graves just as the nuclear bomb explodes.
The game ends with a satellite surveying the detonation area and listing Duke Nukem as killed in action, to which Duke replies off-screen "What kind of shit ending is that? I ain't dead, I'm coming back for more!". A short scene after the ending credits depicts a press conference, where Duke announces his intent to run for the 69th President of the United States.
