Tomodachi Collection takes place on an island in the middle of the sea, that can be populated with various Miis created from the built in Mii Maker, or transferred wirelessly from a Wii console. These Miis can be given a personal voice and personality based on the player's liking.

The cast consists entirely of user created Miis. Players can transfer Miis directly from their Wii console to their Nintendo DS or create new ones using the in-game Mii Maker. The player chooses their looks and personalities then help them with their problems, such as making friends and performing everyday tasks, as well as giving them clothes, food, and special items to help them gain experience. The Miis can interact with each-other in relationships, such as friendships. When a Mii gains enough experience, they level up and collect rewards. New areas and shops are unlocked on the island by playing the game and meeting various conditions, such as the Question Hall, where the player can ask the Miis anything as well, as making them vote on a certain choice.