In the single-player campaign, the player assumes the role of hero Sam "Serious" Stone in his adventures against the forces of the extraterrestrial overlord, "Mental", who seeks to destroy humanity. Taking place after the events of Serious Sam: The Second Encounter, Sam travels through various worlds collecting parts of a medallion in an effort to defeat Mental. He is guided by the Sirian Great Council and receives sporadic aid from the natives of the worlds he visits.