Madden NFL 06 is the second game in the series to appear on the Nintendo DS. Based on the previous year's iteration, it updates the team rosters for the new season, and adds improved graphics, new playing modes and additional touchscreen controls.

Returning modes from the previous game are exhibition games, full seasons, Two Minute Drill, practice and situation. The Madden Cards card collecting feature also returns, as does wireless one-on-one multiplayer. Several new modes that are regular features of the console versions have been added: Franchise, Custom League and Tournament. In addition, there is now the possibility to create both new teams and new plays. The Mini Camp mode adds a number of mini games that can also be played via wireless multiplayer. They include kicking, passing, running, tackling and an obstacle course.

As in the previous game, the in-game graphics are fully polygonal, play calling can optionally be done via the touch screen, and during a play, a real-time Xs-and-Os-style overview of the situation is displayed on the lower screen. New uses of the touch screen include a new kicking interface that asks the player to draw a line fast (for power) and straight (for accuracy). During standard plays, icons to call audibles, hot routes or time outs have been added. Finally, there is optional touch screen passing, with the quarterback aiming the pass at the point tapped.