Volume 1

On his first day at Deimon High School, Sena Kobayakawa hopes to start fresh after years of gofering for bullies and hiding behind his childhood friend, Mamori Anezaki. Three delinquents corner try to beat him up in a rundown shed, but the trio are scared off by an upperclassman named Ryokan Kurita. Sena learns that Kurita is the lineman for the school's struggling American football team, the Deimon Devil Bats, and that the shed is their clubhouse. As he and Kurita converse over cake and tea, Sena's curiosity about the sport grows. He asks to join as the team's manager and the two befriend each other.

The delinquent trio jump Sena on his way home, but he manages to fight them off and a chase ensues. Sena uses the superhuman speed and agility gained from gofering to evade his pursuers, while Youichi Hiruma—the Devil Bats' quarterback and school shadow tyrant—follows eagerly from a distance. Sena dives into a subway car and escapes the trio, whom Hiruma humiliates by stripping them naked and taking photos.

The next day, Hiruma presents Sena to Kurita, all tied up and terrified. He forces Sena into a player's uniform and armor, along with a tinted visor helmet. Hiruma tells Sena that he is their new running back and that he must hide his identity, and thus christens him "Eyeshield 21." Meanwhile, the delinquents find Hiruma's blurred photos plastered around the school, with a written threat to reveal their faces if they bully Sena again.

After lying to Sena about holding a morning staff meeting, Hiruma gleefully drags him onto the field for practice. Kurita and Hiruma walk Sena through two practicing basics: rope ladder drills and a 40-yard dash. Kurita runs for a sluggish 6.5 seconds, while Hiruma runs for 5.1 seconds and proclaims that it's his best time. Sena runs for 5.0 seconds, but Hiruma knows that he can run faster. So he sticks a dog biscuit down Sena's collar and has a ferocious dog named Cerberus chase him, bringing his time down to an incredible 4.2 seconds.

To gather at least eleven players for tomorrow's game, Hiruma proposes that he, Sena, and Kurita recruit three fill-ins each. Those who find nobody are given a "penalty game." Sena and Kurita struggle to find volunteers, but Hiruma deftly recruits 17, first by blackmailing pervy basketball players Yamaoka and Satake, and the rest by bribing them with the promise of cute cheerleaders.

Later on, Sena successfully recruits track runner Tetsuo Ishimaru after helping him deliver magazines around town, but Kurita comes back empty-handed. As a "penalty game," Hiruma makes Kurita carry everyone else's game equipment, which he does with little effort.

The Devil Bats arrive at the game and meet their opponents, the Koigahama Cupids, who are known for bringing their girlfriends to every game. Quarterback Kaoru Hatsujou mocks the Devil Bats for having no girls to cheer them on. The fill-ins get angrily impatient for the promised cheerleaders, so Hiruma bribes the Cupids' girlfriends to cheerlead by promising a meeting with popular teen idol and Oujou White Knights wide receiver Haruto Sakuraba. As it so happens, Sakuraba and his stoic teammate Seijuurou Shin have just arrived to film the game.

When Hiruma spots Sakuraba and Shin with their camcorder, he warns Kurita that they can't put Sena in the game until they leave, as Shin is an absurdly skilled linebacker who would plan a counter-strategy. During the largely uneventful game, Ishimaru slips and twists his ankle whilst failing to stop the Cupids from scoring a field goal. Upon noticing that Sena gave him the wrong cleats to wear, Hiruma yells at Sena and drags him behind the nearest building. A moment later, Sena dashes back out, dressed as Eyeshield 21 and poised to cover for his injured teammate.

Mamori grows anxious about Sena working under Hiruma, so she hurries to the game to check on him. To prevent Sena from being filmed, Hiruma points Sakuraba out to the cheerleaders and they stampede towards him. Sakuraba hands Shin the camcorder and runs off, but Shin runs right after him after accidentally breaking it.

With only nine seconds left in the game, Hiruma relays the final play to Sena: Hiruma will catch the ball during the kickoff and pass it to Sena, who will then run to the Cupids' end zone for a touchdown. Sena frets that he's too weak to hold them back, but Kurita and Hiruma reassure him that he doesn't need strength, only speed. Sena catches Hiruma's pass, but runs in the wrong direction and slips while trying to turn around. Hatsujou smugly walks over, but Eyeshield 21 re-emerges and speeds right past him.

Sena zig-zags around three more of the Cupids players standing in his way. Hatsujou commands three more teammates to block, but Sena uses a spin dodge move to weave around them. Four more of the Cupids surround him near the end zone, but Hiruma and Kurita block two just in time. Sena runs past the last two and scores a touchdown, thereby securing the Devil Bats' first-ever victory with a score of 6-3.

Hiruma urges Sena to get back behind the building after he overhears Mamori asking the fill-ins where he is. Sena haphazardly rushes back, gets re-dressed and resumes his position, in time for a tearful Mamori to find him exhausted, dirty, and lying on the ground. Just as the game ends, Mamori pulls Sena behind her and calls Hiruma out as she brims with anger.