Born in Kyoto, Japan, Sakai grew up in Hawaii and studied fine arts at the University of Hawaii. He later attended the Art Center College of Design in Pasadena, California. He and his wife, Sharon, presently reside and work in Pasadena.
He began his career by lettering comic books (notably Groo the Wanderer by Sergio Aragonés and Mark Evanier) and became famous with the creation of Usagi Yojimbo, the epic saga of Miyamoto Usagi, a samurai rabbit living in late-sixteenth and early-seventeenth-century Japan. First published in 1984, the comic continues to this day, with Sakai 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" that is featured in the Volume 11 trade paperback edition of Usagi Yojimbo). He also created a futuristic spinoff series Space Usagi. His favorite movie is Satomi Hakkenden (1959).
Sakai was the artist for the back-up feature in the trade paperback of Stupid, Stupid Rat Tails.
From 1993 through 2005, Stan Sakai has received twenty-one Eisner Award nominations. He has also been nominated for the Comics Buyer's Guide Award for Favorite Writer in 1999 and 2000.