While in search of his precious friend, a young boy named Nai falls captive to a beautiful woman, whose looks are matched only by her taste for human flesh. Meanwhile Gareki, a clever thief, is in the midst of robbing her luxurious home. After causing a distraction, Gareki agrees to help Nai escape, but they are discovered upon the woman's return. As she transforms into a ghoulish monster, the boys flee. On the run, Nai and Gareki are found by Circus, a government defense agency that deals with criminal activity too difficult for the police to handle and protects civilians from varuga—terrible monsters that devour humans for sustenance. In the hope that it will lead Nai to his missing friend, he and Gareki decide to join Circus. On their perilous journey, they face dangerous varuga and begin to uncover the secrets behind a shadowy organization known as Kafka.

Shun Hashimoto is an openly gay aspiring novelist living in Okinawa who was abandoned by his parents after coming out to them. Mio Chibana is a reserved, orphaned high school student, often found spending his time by the sea. One day, the two meet on the beach, and Shun is instantly captivated by Mio. The days fly by as they slowly begin to grow closer until Mio suddenly announces that he has to leave for the mainland. Three years pass before a 20-year-old Mio returns to Okinawa to confess his love to Shun. However, in those three years, Shun's life has changed. Will he be able to accept Mio's feelings and make such a commitment?

Yoshikazu Miyano's troubles first start one hot summer day when Shuumei Sasaki steps into his life. Sasaki saves Miyano's classmate from a group of bullies, and after that, Miyano cannot seem to shake off his eccentric upperclassman. His silent admiration for Sasaki gradually sours into annoyance each time the so-called delinquent refuses to leave him alone. Constantly being called by cute nicknames and having his boundaries ignored, Miyano wonders why Sasaki wants to get close to him. The shy and easily flustered Miyano harbors an embarrassing secret—he is a fudanshi, a boy who likes boys' love (BL) manga. The last thing he wants is for other students to find out, but through a slip of the tongue, he reveals the truth to Sasaki. Intrigued, the clueless Sasaki asks to borrow a book to read, which he is given very reluctantly. To Miyano's surprise, Sasaki enjoys the BL that he receives and asks for more, marking a shift in their strange dynamic. Although Sasaki appears to possess some personal agenda, his feelings for Miyano become complicated the more time they spend together. As they now share a common interest, their relationship is poised to change and further develop.

Shy, reserved, and small-statured, Deimon High School student Sena Kobayakawa is the perfect target for bullies. However, as a result of running errands throughout his life, Sena has become agile and developed a skill for avoiding crowds of people. After the cunning Youichi Hiruma—captain of the Deimon Devil Bats football team—witnesses Sena's rapid legs in motion, he coerces the timid boy into joining his squad. As Hiruma wants to conceal Sena's identity from other clubs, Sena is forced to hide under the visored helmet of Eyeshield 21, a mysterious running back wearing the number 21 jersey. The legendary Eyeshield 21 can supposedly run at the speed of light and has achieved remarkable feats in the United States during his time at the Notre Dame College. Accustomed to avoiding his problems in the past, Sena's specialty might just help him become the new secret weapon of the Deimon Devil Bats. As he interacts with his teammates, Sena gradually gains more self-confidence and forges valuable bonds along the way.