de Blob 2's gameplay is largely similar to its predecessor's. The player once again controls Blob, who can mix colors in order to paint objects and bring life to the cityscape, which in turn opens up previously locked areas. Blob is given missions by his friends in the Color Underground, such as completing timed races, defeating enemies, liberating captured Graydians and seizing important landmarks.
However, new gameplay additions have been added. One example is Blob's new ability to perform a powerful dash attack, which breaks through obstacles and kills most foes, at the expense of a sizable number of paint points. Furthermore, as the player progresses through the game, they obtain "inspiration points", which are used at the Idea Emporium to purchase upgrades for Blob, such as increased paint capacity and defensive shields. Power-ups feature within the levels as well: the magnetic Wrecking Ball allows Blob to roll up metal surfaces, sink underwater, and destroy any enemy easily; the Hazmat Suit protects Blob from any passive hazards such an ink and hotplates; the Graviton Bomb temporarily transforms Blob into a devastating black hole; the Re-Gen constantly replenishes Blob's paint points; and the Rainbow gives Blob infinite paint points and gives him the use of all seven colors at once.
Another new inclusion is a two-player mode akin to the co-op functionality of Super Mario Galaxy. The second player takes control of a new member of the Color Underground named Pinky, who is able to assist Blob and help him surmount more difficult challenges. Bosses also play a larger role in this game; the player has to use the painting mechanics in thoughtful ways in order to defeat them.
Aside from the new gameplay additions, de Blob 2 also has a heavier emphasis on platforming compared to its predecessor. Much like in de Blob, Blob has to take over landmark buildings in the city, but this time he also has to enter them, rather than simply needing a certain number of paint points to capture it. Inside, the gameplay switches from its usual 3D perspective to a 2D perspective. Blob must then complete a platforming challenge filled with many hazards, such as the new Gravity Wall mechanics, before the building is taken. There are over 100 of these platforming stages throughout the course of the game.
In comparison to the home console versions, the Nintendo DS version of de Blob 2 instead plays entirely as a 2D platformer. It is divided into individual levels that require Blob to make use of wall jumping and a slingshot technique to traverse environments, with these features drawing comparisons to the gameplay used in the Sonic the Hedgehog series.[