Zack & Wiki is presented as a third-person perspective adventure game, with the player controlling the actions of Zack through the Wii Remote. The player can point to objects on the screen, identified by a cursor, to have Zack investigate the item or move about the level. Enemies in the level can be transformed into usable items by having Zack shake his companion Wiki like a bell. When the player has Zack interact with a usable item, the game shifts to a first-person view, and the player must mimic the operation of the item with the Wii Remote. For example, to cut down a tree with a saw, the player holds the Wii Remote horizontally and moves it back and forth. Successful actions are awarded points based on the cleverness of the action, how many attempts it takes to perform the action correctly, and the difficulty level.
Zack aspires to be the greatest pirate ever. He and his "enchanted" friend Wiki are the newest members of the pirate gang, "The Sea Rabbits". On their flight to the Sea Rabbits' hideout, Zack and Wiki crash land on an island. On the island, however, they find a treasure chest with the golden talking skull of the legendary pirate captain Barbaros who promises to lead them to his famous Treasure Island and give them his Legendary Ship if they will restore his body, by collecting the various pieces of his body scattered around the area.
Zack and Wiki search through several areas of the world, each one containing either a missing piece of Barbaros' cursed self, or a map leading to other areas. While they explore these areas, they frequently run afoul of the Rose Rock Pirates, a group led by the bourgeois Captain Rose and crewed by her band of seemingly indestructible Goons.
