Timid, diminutive, and frequently the target of bullies, Sena Kobayakawa has just enrolled at Deimon Private High School. When he angers a group of delinquents by refusing to act as their errand boy, he makes an incredibly speedy getaway, an ability he has developed through years of running from his tormentors.

Youichi Hiruma—the demonic captain of the Deimon Devil Bats football team—happens to be nearby, and seeing Sena's "golden legs" at work, forcibly recruits him as a running back despite Sena's desire to be team manager instead. Made to don the number 21 jersey and a special helmet to hide his identity as a player, Sena becomes "Eyeshield 21," the team's closely guarded secret weapon. Soon he realizes his love for the sport, and aims to help the Devil Bats reach the Christmas Bowl, the high school football championship.