Sorkin began her career in New York City cabarets in the late 1970s and early 80's as a member of the comedy group "The High-Heeled Women". (Her fellow members were Mary Fulham, Tracey Berg, and Cassandra Danz.) Later, she went on to be the original female co-host on America's Funniest People. She also wrote for Tiny Toon Adventures.
One of her more prominent roles was the wacky but lovable Calliope Jones, as seen on Days of our Lives. She played this part from 1984 to 1990, and even made return visits in 1992 and 2001. On February 24, 2006, she reprised her role on the soap for the fourth time.
Many comic book fans know her as Harley Quinn, the Joker's ditzy sidekick. Paul Dini, a friend of Sorkin's who created Harley for the TV series Batman: The Animated Series, has said in several interviews that he based Harley on her personality and asked her to play the part. Harley later appeared in the 2002 one-shot comic book Batman: Harley Quinn. Her character also appeared in other animated television shows The New Batman Adventures, Static Shock, and Justice League, as well as Gotham Girls, an internet cartoon series.
Lesser known is her work on the series Frasier. (Her husband Christopher Lloyd was the producer). On the show, Sorkin would perform as a caller to Frasier Crane's radio show; the lines would later be dubbed over by a celebrity caller. In the final episode of Frasier, Sorkin had an onscreen part as the owner of a monkey.