In Sanctum, players take on the role of Skye, an elite soldier sent out to protect her home town, Elysion One, from hordes of mysterious alien creatures.

These towers include stationary weapons, teleporters for the player's use, and pads that affect enemies moving over them.

Unlike most tower defense games, the player is allowed to move about the level during this phase and attack enemies with different weapon types, much like in a typical first-person shooter.

To aid the player in this, information about upcoming waves is shown in the pause menu, as well as descriptions of the various enemies, towers, and weapons.

This variation of enemy traits forces the player to construct different tower types in order to mount a successful defense.