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Since the mid-1980s, he has worked as a theatre actor and director in New York City and played small roles in television and film productions. Among other things, he directed a play by Tennessee Williams. From 1991, he appeared in the original Broadway production of Marsha Norman and Lucy Simon's musical adaptation of The Secret Garden, which won several Tony Awards.

In the early 1990s, together with musician Stephen Trask, he developed the character of Hedwig, a transgender rock musician who grew up in East Berlin, for performances in the New York drag bar Squeezebox. This led to the successful Off-Broadway musical Hedwig and the Angry Inch in 1998, which won two Obie Awards, and three years later to the film version of the musical, again with himself in the title role. The film premiered at the 2001 Sundance Film Festival, where it won the Director's and Audience Awards, and the play won the 2001 Lambda Literary Award. At the 2002 Chlotrudis Awards, he won the prize for best leading actor. At the Berlin International Film Festival (Berlinale) in 2001, the film was shown in the ‘PANORAMA’ section and won the Teddy Award.

In 2003, he produced the film Tarnation by Jonathan Caouette, which was honoured as best documentary film by the US National Society of Film Critics, among others. In 2004, Mitchell shot the music video for the Scissor Sisters' single Filthy/Gorgeous with stars from the New York drag scene. The clip was not shown on American MTV due to its explicit sexual depictions.