Sena Kobayakawa has just started at a new high school, and he's already getting picked on by bullies. Fortunately, he has a secret weapon: his incredible speed. It's not long before the captain of the school's American football club, Yoichi Hiruma, notices Sena's talent and forcibly recruits him as the team's running back under an alias: Eyeshield 21. Based on the Eyeshield 21 anime, Max Devilpower! follows Sena and the Deimon Devil Bats as they recruit new members for the team while facing off against the best of Japan's high school division of American football.

The game is mostly made up of cutscenes following the Devil Bats' climb to the top, with training sessions, mini-games, and matches making up the game's action. However, Max Devilpower! doesn't play as many traditional American football games do. Instead of controlling most of the action on the field, matches are comprised of strategic planning which lead into mini-games that test reflexes, such as tapping the ball with the Nintendo DS stylus to catch it or tapping a route with the stylus to dodge incoming players.

Playable teams include the Deimon Devil Bats, Koigahama Cupids, Ojo White Knights, Zokugaku Chameleons, Seibu Wild Gunmen, Taiyō Sphinx, and a team hailing from America, the NASA Aliens. Another team, Kyoshin Poseidon, can be unlocked by having Eyeshield 21: Devilbats Devildays in the Nintendo DS Lite's Game Boy Advance slot.