"Murderous aliens have landed in futuristic Los Angeles, and humans suddenly find themselves atop the endangered species list. The odds are a million-to-one, just the way Duke likes it!"
Having managed to escape from (and destroy) the Rigelatin spaceship at the end of Duke Nukem II, Duke thinks things should be quiet for a while, but he's wrong. His sky car is shot from the air, and Duke is forced to eject onto a rooftop in Los Angeles. Angry that his ride has been shot up, Duke loads his pistol and goes shooting.
He blasts his way through numerous different locations, including strip clubs, prisons, submarines, space stations, flooded cities, military bases and fast food restaurants, and destroys every alien he comes across.