In 2010, Harris won two awards at the 62nd Primetime Emmy Awards, winning for Outstanding Guest Actor in a Comedy Series for his guest appearance on Glee, and Outstanding Special Class Program for hosting the Tony Awards in 2009 he has won the latter award three additional times for hosting the show in 2011, 2012, and 2013. He also hosted the Primetime Emmy Awards in 20, and hosted the 87th Academy Awards in 2015, thus making him the first openly gay man to host the Academy Awards. In 2014, he starred in the title role in Hedwig and the Angry Inch on Broadway, for which he won the 2014 Tony Award for Best Leading Actor in a Musical. Harris was named one of Time magazine's 100 Most Influential People in 2010.

Harris began his career as a child actor and was discovered by playwright Mark Medoff at a drama camp in Las Cruces, New Mexico. Medoff later cast him in the 1988 drama film Clara's Heart, starring Whoopi Goldberg and based on the novel of the same name by Joseph Olshan. Clara's Heart earned Harris a Golden Globe nomination. The same year, he starred in Purple People Eater, a children's fantasy. Harris's first film role as an adult was 1995's Animal Room, although he portrayed a teenager. His subsequent film work has included supporting roles in The Next Best Thing, Undercover Brother, and Starship Troopers.