While putting herself through college at Hofstra University, she worked as a Playboy bunny. She got her start in acting in the 1960s, playing opposite Dustin Hoffman in the Broadway play Jimmy Shine. From there, she played parts in daytime dramas. Starting with a part on A World Apart in 1970, she moved to a five year stint as Lenore Moore Curtin Delaney on Another World. Taking over the role from Judith Barcroft, Sullivan played the role from 1971 to 1976, and it was this role that first established her as a household name. In 1977, Susan played Dr. Elaina Marks in the Incredible Hulk TV Series pilot, and in 1979, she appeared as Vice-Admiral Lori Ciana in Star Trek: The Motion Picture, though her entire part consisted of her character being killed in a transporter accident.

An Emmy nomination for her role as Maggie Porter in the television drama Rich Man, Poor Man: Book II brought her even more attention. Her role as Dr. Julie Farr in Having Babies, which was made into two television movies and later a weekly series, was much ballyhooed but, in the end, proved unsuccessful as a TV series. In 1980, she wished to restart her career by appearing on the sitcom It's a Living. This role led to a successful audition for Falcon Crest. At first, Sullivan turned down the role, but accepted when the producers insisted.

The role of Maggie brought her back into the limelight and was her most successful role to date, acting on the series from 1981 to 1989. When Sullivan wished to leave the show, the writers of the series had her exit in dramatic fashion, with Maggie drowning at the bottom of the family pool, the result of her wedding ring being caught in the pool drain after she tried to fish her son's toys out. Until her character was killed off, Sullivan had appeared in every episode of the series (out of the 227 episodes produced, she had appeared in the first 207).

Sullivan drifted out of the public consciousness again, with appearances on The George Carlin Show and the political drama The Monroes in the early and mid-1990s. However, it was not until a supporting role in the movie My Best Friend's Wedding (as the mother of Cameron Diaz's character) that ABC executives were interested in Sullivan for a part on a new sitcom, Dharma and Greg. She played the snooty country-club matriarch Kitty Montgomery on the series from 1997 to 2002 and gained a new audience altogether. She also has a recurring role on Justice League Unlimited as Queen Hippolyta.

She has never married or had children, but her partner for over fifteen years has been psychologist and author, Connell Cowan. She also previously dated, among others, the late film star, Cary Grant.

For many years, she was the spokeswoman for Tylenol brand pain reliever.