The game board depicts four major towns: Arkham, Innsmouth, Dunwich and Kingsport. On each turn, a player can use up to a specified number of actions (dependent on the character card) to travel between cities, defeating cultists, killing shoggoths, or sealing a portal. A deck of cards provides the players with these abilities, but sprinkled throughout this deck are Old Stir cards that accelerate and intensify cultist and shoggoth activity. Once an Old Stir card is revealed, an Old One card then has to be revealed which hinders your gameplay and putting you one step closer to death by Cthulhu.
Taking a unique role within the team, players must plan their strategy to mesh with their specialists' strengths in order to conquer the reign of Cthulhu. For example, the Hunter can defeat all cultists in that city when taking a defeat cultist action and is able to kill a shoggoth with one action instead of three; the Detective is able to seal a portal with one less resource (4 cards instead of 5)—but the monsters are being summoned one after another and time is running out. If more than three shoggoths overrun you or you meet the Old One Cthulhu, all players lose. If all four portals are sealed, they all win!