According to lead game designer Eric Holmes, after the completion of The Incredible Hulk: Ultimate Destruction, Radical Entertainment pitched two different games as a follow-up. The first pitch was a direct sequel for the Xbox 360 and PlayStation 3; not much is known about the sequel other than that it was planned to be bigger in scale. The other pitch they considered was making a game based on the 2002 limited comic miniseries "The Ultimates", and would have featured Iron Man, Thor, Captain America and Quicksilver as playable characters. With Activision acquiring Radical however, both of these projects never came to reality.

The developers aimed to design the game in a "hyper realistic" art style, and the specific visual design of the Hulk was based on the Ultimate Earth-1610 version of the character as he appeared in the limited comic series "The Ultimates". Bryan Hitch, an artist on The Ultimates comics, was brought on as the game's character concept artist because the developers were fans of the miniseries.