One day, Dunk, the magic magician of Bubble World, releases a spell that transports eight characters from their home worlds to Bubble World. Now it is the player's turn to bring them back home!

In Puzzle Bobble 64, you must try to remove all the bubbles in each stage by connecting three or more of the same color.

Five playing modes are available:

Arcade mode.
Challenge mode: in this mode the player's performance is evaluated and the game adapts to it.
Win Contest mode: challenge all eight characters.
Collection mode: a collection of levels created by Bust-A-Move players. Each round carries the designer's name.
Edit mode: players can create and play their own puzzles.

The Nintendo 64 version also includes two- and four-player modes.