Picking up where Serious Sam: Second Encounter left off, Sam has rocketed off towards the conquered planet of Sirius, the new home of the notorious Mental. While en route, the Great Wizards Council of the nearly eradicated Sirian civilization telepathically contacts Sam to aid him in his quest to destroy Mental and help restore Sirius. He is then sent on a quest to find the fragments of a mystical medallion scattered throughout the galaxy that will bestow Sam with the power to defeat Mental.