Sonic is back, and this time, he needs the help of all of his friends to defeat the evil Dr. Eggman. In Sonic Advance 3, Sonic and Tails must reunite with their friends Cream, Knuckles, and Amy. Team up with any of the five characters to gain special attack moves: Sonic increases your speed, Tails increases your jump power, Knuckles increases your attack power, Amy offers the Piko Piko hammer attack, and Cream lets you perform a homing attack. With a Game Boy Advance link, you and three of your friends can battle it out in multiplayer modes.

Prior to the game's events, Doctor Eggman builds a robotic assistant named Gemerl, using parts from the robot Emerl who was destroyed in Sonic Battle. Eggman attempts an experiment using the Chaos Emeralds to perform the Chaos Control technique, but it goes awry and tears the world apart. This action separates Sonic and Tails from Amy, Knuckles, and Cream, all of whom Eggman finds and captures, intending to create a segment of his impending empire on each chunk of the planet. Sonic and Tails travel through the game's seven levels to recapture their friends and retrieve the Emeralds.

The final boss fight takes place at the Altar Emerald temple. If the player defeats Eggman there without having all seven Chaos Emeralds, Eggman and Gemerl escape and fall off the edge of the temple. Peace is restored to the world, and Omochao snaps a picture of the five heroes. However, the game alerts the player that the Emeralds must still be collected for the true ending. If the player defeats Eggman at the temple with all the Chaos Emeralds, Gemerl stops running away with Eggman and attacks Sonic, causing the Emeralds to scatter. Gemerl uses them to take on a giant, orb-shaped form, but Sonic also uses their power to attain his Super Sonic form. With Eggman's help, Super Sonic destroys Gemerl. Tails later finds Gemerl's broken body on a beach, repairing and reprogramming it. The game ends as Cream plays with the now non-aggressive Gemerl at her mother Vanilla's house.