The anime has been watched by a large number of television viewers in Japan, helping to raise American football's popularity in the country. The manga and anime have been featured at various times in weekly top ten lists of best-selling in their respective media. In Japan, the Eyeshield 21 manga has sold over 20 million volumes.

The whole series was streamed in English by Crunchyroll, while Sentai Filmworks licensed the series, with distribution from Section23 Films on DVDs. The anime series was later licensed in North America by Toonami Jetstream as a joint effort with Viz Media and aired on December 17, 2007, on its site, but before its completion, the streaming service was shut down. In North America, the manga was released by Viz Media from April 2005 to October 2011. The Eyeshield 21 franchise has spawned two original video animations (OVAs), audio albums, video games, and other merchandise. The television series first aired on Japan's TV Tokyo network from April 6, 2005, to March 19, 2008.

An anime adaptation consisting of 145 television episodes was co-produced by TV Tokyo, NAS, and Gallop. The series consists of 333 chapters collected in 37 tankōbon volumes. The manga was originally serialized in Shueisha's Weekly Shōnen Jump from July 2002 to June 2009. Inagaki chose American football as a central subject of Eyeshield 21 after realizing that it fit perfectly with his idea for the series. The series tells the story of Sena Kobayakawa, an introverted boy who joins an American football club as a secretary, but after being coerced by Yoichi Hiruma, turns out to play wearing an eyeshield and the number 21, under the pseudonym of 'Eyeshield 21'. Eyeshield 21 (Japanese: アイシールド21Hepburn: Aishīrudo Nijūichi) is a Japanese manga series written by Riichiro Inagaki and illustrated by Yusuke Murata.

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