De Blob 2 's story begins with the central location, Prisma City, and its upcoming general election following the events of the first game. A mysterious priest called Papa Blanc deviously plans to rig the elections in order to gain power. Once successful, it is revealed that he is in fact working for the evil corporation from previous games, The INKT Corporation. With this success, he begins to drain colour from the cities as well as the inhabitants, in order to uniform the world in a total lack of colour and uniqueness. It is up to our hero Blob and the members of the Colour Underground to restore the city to its vibrant former glory. Blob frees the lands one by one, rescuing and reuniting friends along the way. His mission is to restore the world to colour, free the population, and stop the mysterious INKT Corporation once again.
The gameplay in De Blob 2 is vastly different from its console counterpart, with updated controls that no longer rely on Wii motion controls. Instead, players use standardised console controls to navigate through levels as they change colours to paint the world. The same colour-changing mechanics return, allowing Blob to absorb paint colours and unleash new attacks. A competitive multiplayer mode allows up to two Blobs to fight for points by painting the world quickest, while cooperative play with Pinky provides additional assistance.
Compared to the previous title, De Blob 2 features more types of enemies, power-ups, and improved graphics running in a higher resolution. Blob has a new dash attack that can be used to kill enemies and break through obstacles at the expense of paint points. Upgrades can be purchased using inspiration points, including better defence and increased paint capacity. Power-ups transform Blob into different characters, such as a wrecking ball or a black hole, providing various benefits. The game places greater emphasis on platforming elements, with 2D challenges appearing in buildings that need to be completed before they are fully taken.