Born in Chicago, Lee Lewis spent six years in Zimbabwe before moving with her family to Australia in 1977. She spent the remainder of her childhood in the New South Wales regional city of Goulburn and began her stage career with Goulburn's Lieder Theatre. After graduating from NIDA, Lewis spent the 1990s in New York. She worked on and off Broadway and studied fine arts at Columbia University before returning to Australia to continue her career in directing.
In 2012, Lewis was appointed artistic director of Griffin Theatre, Sydney. In 2019, she became the artistic director of the Queensland Theatre Company, a role she continued through the challenging pandemic years. She stepped down from this role at the end of March 2024, whereupon the three Associate Artistic Directors undertook the artistic oversight of the remaining 2024 season: Daniel Evans (Programming), Isaac Drandic (First Nations) and Fiona MacDonald (Education and Youth).