In 2002, Janet Varney co-founded the long-running live comedy showcase SF Sketchfest in San Francisco.
Varney was co-host of The Hollywood Show with Brian Unger, a recurring player on Norm MacDonald's sketch show Back to Norm and an ensemble player on Crossballs, all for Comedy Central. She also starred in the short-lived FOX comedy Happy Hour. In 2007, Varney appeared in the short films Random Acts of Kindness, Die Hardly Working, Eternal Waters, Worldly Possession, The Losers, Keep Off Grass, and Dress For Success which were made during the reality show On the Lot. She later appeared as recurring character Bev for the web series Back on Topps with Randy and Jason Sklar. Starting in 2008, she began starring in the HBO television series Entourage, playing television producer Amy Miller. Varney was also cast in a movie called Best Player, starring opposite Jerry Trainor and Jennette McCurdy.
In 2005, Varney replaced Lisa Kushell as the hostess of the TBS cooking and entertainment show, Dinner and a Movie. Since then, she has appeared, alongside host Paul Gilmartin and chef Claud Mann, in each episode introducing movies and injecting humor during the preparation of a creative dinner to go with some theme of the movie.
In 2012, Janet Varney became a regular cast member of the reality show parody Burning Love. In 2016, Varney co-starred in the dark TV comedy Stan Against Evil, created by Dana Gould.