John was born in Hazlehurst, Mississippi. He took lessons in classical piano from an early age. After high school he enrolled at Belhaven College in Jackson, Mississippi. After graduating from Belhaven he got a job playing piano in Colorado, but in 1978 he moved to New York and became a rehearsal pianist for the American Ballet Theater. In addition he began doing drag performances at nightspots such as Club 57 and the Pyramid Club.
He is mainly known for creating his stage character Lypsinka. As Lypsinka he is lip-synching to meticulously edited show-length soundtracks culled from snippets of outrageous 20th-century female performances in movies and song.
Lypsinka first met her public in late 1988 when Epperson's act was a late-night addition to the bill of Charles Busch's Vampire Lesbians of Sodom at the Provincetown Playhouse in New York. She has appeared in evening-length solo shows Off-Broadway, including The Boxed Set and As I Lay Lip-Synching. According to Epperson, the prototype for Lypsinka is Dolores Gray.
John Epperson is a frequent performer at Wigstock. Epperson has also performed an autobiographical solo cabaret show, Show Trash (2004), out of drag, talking and singing in his own voice.
In Winter 2004, Epperson (in a different drag role) played the role of the Wicked Stepmother in the New York City Opera's revival of Rodgers & Hammerstein's Cinderella in a cast with Eartha Kitt, Dick van Patten and fellow Wigstock veteran Renee Taylor.
Epperson provided a commentary track for the 2006 "Special Edition" DVD release of What Ever Happened to Baby Jane?, along with Charles Busch. The second disc of the set also contains a short feature about Bette Davis and Joan Crawford, titled 'Blind Ambition', with contributions from Busch and Epperson.
He has also written a play, My Deah, his version of the Medea tale transplanted to Mississippi which debuted at the June Havoc Theater in New York (2006).
Lypsinka played Mrs. Wilson in Another Gay Movie.