In Amoeba Wars, players play remnants of a fallen galactic civilization returning to its home sector, which had been overrun by space amoebae.

Starting from corners of a hexagonal board, players direct fleets of ships to capture solar systems and push back amoeba infestations and renegade doomsday machines (relics of the empire), trying to control the central solar systems and retake Saestor, the old homeworld, at the center of the board.