Sakai 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. Usagi Yojimbo started out as a small drawing in his sketchbook. Many of his characters were inspired by Japanese history and fiction. Stan based his main character on the samurai Miyomoto Musashi. Another notable reference to Japanese fiction is his character Zato Ino the blind sword pig, who is an homage to the great Zatoichi of the silver screen
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.
Sakai also created a futuristic spinoff series Space Usagi. Stan Sakai's character Usagi has also made numerous appearances alongside the Teenage Mutant Ninja Turtles.
Stan was born in Kyoto, Japan, yet grew up in Hawaii. Stan received his Fine Arts degree from the University of Hawaii and furthered his studies at Art Center College of Design. It was his older brother Ed who got him into reading comic books. He now lives in San Diego, California and is a mainstay at both Comic and Anthropomorphic Conventions; including being a featured guest at Anthrocon in Pittsburgh, PA for several years and the Guest of Honor at the inaugural Antheria, to be held in Los Angeles, CA in October of 2010. Stan has also received awards such as the Parents' Choice Award, the Inkpot Award, the American Library Association Award, two Spanish Haxtur Awards, three Eisner Awards, and the National Cartoonists Society Comic Book Division Reuben Award.