The Madden series makes its first appearance on the PSP with Madden NFL 06. Based on the concurrent console version, it adapts some of its modes for play on the handheld, removes others, and adds some unique features, including several mini games.

Gameplay modes include exhibition games, wireless head-to-head play (online or ad-hoc), practice, and franchise. Modes and features that have not made it over from the consoles include owner mode, superstar mode, Madden Cards, creating teams, or the ability to challenge plays. The new gameplay features QB vision or hit stick (due to lack of a second analog stick) are not in the PSP version either, but precision passing has made the cut. The game also features connectivity to the PS2 version: it is possible to transfer franchise games from PS2 to PSP and vice versa, allowing one to play one set of games at home and another on the road, with results available on both systems.

The Mini Camp mode from the console version has been expanded and features ten exclusive mini-games, playable either on their own or in a competition. Another PSP-exclusive feature is an assistant coach mode.