Serious Sam: Second Encounter introduces three worlds where cyberpunk once again meets fantasy fiction, and features frantic action in 12 massive single player levels. The Second Encounter includes three new episodes based in beautifully detailed ancient civilizations: South America, Babylon, and The Medieval Age. With fourteen total weapons at his disposal, three brand new, Sam is more serious than ever. He battles against hordes of old enemies and seven adversarial species in an effort to reach the Mental once and for all.

Having successfully defeated the Mental forces in ancient Egypt, Sam "Serious" Stone seizes an abandoned spacecraft. On course in his crusade to finally assassinate the great evil Mental, our hero's spaceship suddenly tumbles into the South American Mountains - Sam seems destined to stay on Earth. He must fight the tougher, now more experienced members of Mental's destructive forces and find a new way to reach the notorious Mental himself.