The first year of NFL license exclusivity is also the first year the Madden series moves onto a new console generation with Madden NFL 06 for Xbox 360. The new hardware powers a new graphics engine that enables higher detail, more animations, lighting and weather changes after every play, and many athletes and coaches modeled after their real-life counterparts. The 360 version also features a redesigned interface, but is missing several features and game modes compared to the previous generation's version.

The included gameplay modes are exhibition games, franchise and online head-to-head games via Xbox Live. Franchise mode has been partly cut down from the previous games: there are no storyline elements like newspapers and radio, and no scouting. Stats tracking is however much more detailed. New 06 gameplay features like the truck stick and quarterback vision are included, even though QB vision is disabled by default. Other features like owner mode, superstar mode, mini camps or player and team creation have not made it to this version. There also is no option to challenge plays.

The playcalling interface has been redesigned and is now sorted into categories, including suggested plays from John Madden or the team's coach as well as formations, play types, key players, or the last five plays run. There is also a new kick meter.