Duke is called into action via the Government, aliens have once again landed and are wreaking havoc. Duke pummels the alien menace through the streets of New York with the help of some Marines, and eventually gains access to the Statue of Liberty. Here, Duke discovers the aliens' true plan, to go back in time and mess with historic events so Earth now wouldn't be what it is and make it so they could easily take over. However, Duke in his fight is teleported to the future, where the aliens have won and the humans are near extinction. In this time zone, Duke battles through horrors of new alien breeds in the future, and the zombified corpses of those who didn't survive the fallout. Duke eventually meets up with the small band of resistance fighters in the old headquarters of the U.S. army in New York. There, they tell him that the aliens are indeed screwing with history, so much that this future is just one; if Duke wants the old one back he'll have to fight for it. The humans have developed their own time machine in order to send a soldier back to re-write history, and destroy the aliens. Duke is sent back to the Old West, where aliens have taken over parts of the American West in an effort to detonate a bomb in Earth's core to destroy the planet.
In the Old West, due to technical difficulties, Duke must make do with period weaponry with the exception of a few of his weapons which his allies can send back. The aliens have begun creating super-soldiers in order to combat Nukem and the humans of the future. After blowing up a ship containing the super-soldiers, Duke makes his way to the town of Roswell. There, he stops the bomb before the aliens can succeed. Duke then is informed, that it's not just America's past that is being altered, the aliens have also been sent to the Victorian Era of London.