Lee is of Chinese ancestry[2] and is long time friends with fellow PFFR member and television producer Vernon Chatman. They met as undergraduates at San Francisco State University.[3] Along with Chatman, Lee is the co-creator, writer, director and star of Wonder Showzen. He voices Wordsworth, one of the main puppet characters and provides various other voices on the show. The pair also co-created Snoop Dogg's 2002 MTV sketch show Doggy Fizzle Televizzle. In addition, Lee is the co-creator of Xavier: Renegade Angel, also with Alyson Levy, Chatman and Jim Tozzi. He also worked as a creative consultant on the Adult Swim series Superjail! in 2009. In 2011, Lee, Levy and Chatman created the Adult Swim mini-series The Heart, She Holler starring Patton Oswalt and Kristen Schaal.
Lee was a member of the now defunct rock trio Muckafurgason. Although his primary role in the band was the bassist, the members of Muckafurgason were often known to "play musical chairs" with their instruments, seeing Lee occasionally turn his hand to lead vocals, guitar and even clarinet.[4] Through Muckafurgason he became acquainted with the band They Might Be Giants, who wrote the song "John Lee Supertaster" about him.
Lee's directorial debut was the 2016 Pee-wee Herman comedy film Pee-wee's Big Holiday. Afterwards, in 2019, he created another CGI show with Kytten Janae in the pilot Di Bibl for Adult Swim.[5] He later then directed the 2021 horror film False Positive.