The young Mike Jones receives a telepathic message from Mica, the princess of the Argonians, whom he had rescued in the previous game. She tells Mike how to decipher a code that he and his uncle Dr. J found on the Argonian space pod. The archaeologist and his nephew read the deciphered message aloud, which teleports Mike into the Stone Age. While helping the natives, Mike discovers a strange object which Mica identifies as a "Tetrad". These Tetrads are scattered across different time periods, and Mike has to find them in order to help the Argonians. However, an unpleasant surprise awaits the hero: the antagonist Zoda appears to be alive and well during the same time period as the famous detective Sherlock Holmes, and is hunting for the Tetrads himself...

Like its predecessor, Zoda's Revenge: Star Tropics II merges action-oriented combat with light RPG elements. Mike will travel to different time periods, communicate with various characters (some of which are real historical figures), solve mysteries, and fight regular enemies as well as bosses. Mike has a larger arsenal of weapons at his disposal this time, including an axe, a dagger, and a katana. He also learns an upgradable projectile magic called Psychic Shock Wave. As in the previous game, Mike's health is measured in hearts; similarly to Zelda games, their amount can be raised during the game.