Resistance: Fall of Man follows an alternate history where the world did not experience World War II, the Great Depression, or the rise of Communism in Russia. An era of peace and prosperity follows the Great War, ending with the revelation of a ruthless and destructive race called the Chimera. The Chimeran virus originates in Russia, which quickly falls to the threat. The Chimera begin to build their army and invasion infrastructure. The world can only guess as to what has happened in Russia. In 1951, the year in which the game takes place, Great Britain finds itself under invasion. Both Asia and Europe have already fallen to the Chimera by this time. Very little is known about the Chimera and their origins remain unclear.
The game follows the story of U.S. Army Ranger Sgt.Nathan Hale, who seems to have somewhat of a resistance to the Chimeran virus in that he does not fall into a vegetative state when infected. He becomes the key figure in a desperate operation that is launched to try to halt the invasion. The next three days are chronicled in the game as the U.S. and British forces band together in a last-ditch effort to save what is left.