In Tokyo, a weak, unassertive boy named Sena Kobayakawa enters the high school of his choice, Deimon Private Senior High School. Sena's only remarkable physical abilities are his running speed and agility, which are noted by the school's American football team captain Yoichi Hiruma. Hiruma forces Sena to join the Deimon Devil Bats football team as its running back. To protect his identity from other teams who want to recruit him, Sena is forced to publicly assume the role of the team secretary and enter the field under the pseudonym of "Eyeshield 21" wearing a helmet with an eyeshield to hide his features.

Takumi, a gifted chef, just landed a new job. He works at the Astro Manor apartment building that offers breakfast, and there he encounters the beautiful landlady—Mira. It’s love at first sight, and he hopes to charm her, but the quirky tenants and bizarre phenomena don’t make it easy. He even learns by pure chance that Mira is secretly an alien! Will their love survive these unearthly oddities?