Stan Sakai began his career by simply lettering comic books as he perfected his art and began working in the industry. He also wrote and illustrated The Adventures of Nilson Groundthumper and Hermy; a comic series with a medieval setting, influenced by Sergio Aragonés' Groo the Wanderer. Stan became famous with the creation of Usagi Yojimbo, the epic saga of Miyamoto Usage, a samurai rabbit living in late-sixteenth and early-seventeenth-century Japan. The story, first published in 1984, continues to this day. It progresses with Stan as the lone author and nearly sole artist (Tom Luth serves as the main colorist on the series, and Sergio Aragonés has made two small contributions to the series: the story "Broken Ritual" is based on an idea by Aragonés, and he served as a guest inker for the black-and-white version of the story "Return to Adachi Plain.")

In 2013, Stan illustrated the limited series 47 Ronin by Dark Horse Comics Publisher Mike Richardson. He also served as an editorial consultant on Lone Wolf and Cub and has contributed to two issues of The Simpsons Treehouse of Horror.

He lives in Pasadena, California.