While performing in a summer of 1981 NU campus productions of Shakespeare's Taming of the Shrew, in which she played Kate, Marg was spotted by a scout for the TV soap opera Ryan's Hope.Soon after completing college, Marg landed her first professional acting role on the long-running ABC Daytime soap opera, playing uptight amateur cop Siobhan Ryan Novak (1982–1986), a role previously played by Sarah Felder and Ann Gillespie.Her performance from 1988 to 1991 on the highly-acclaimed dramatic series won an Emmy Award for Outstanding Supporting Actress in a Drama Series in 1990.Meanwhile, in 1989, Marg made her feature film debut in a leading role as an all-night answering service operator in one segment of the Wheat brothers’ horror anthology After Midnight.After playing a recurring role as George Clooney's love interest on NBC's medical drama ER, Marg became David Caruso's sex-starved widow on Showtime’s Elmore Leonard's Gold Coast, helmed by Weller, and starred as a woman involved with Steven Seagal in the 1997 action film Fire Down Below.
She also starred as Dennis Quaid’s wife and Scarlett Johansson’s mother in writer-director Paul Weitz's romantic drama comedy In Good Company (2004) and appeared on Pond's Smooth Perfection Skin Cream 2005 print ad.
Her performance as the female lead has earned her two Emmy Awards and two Golden Globe nominations.
In 2005, she and her fellow cast members won the Screen Actors Guild Award for Outstanding Performance by an Ensemble in a Drama Series.
She says that she often plays hacky sack with the guys during their free time on set.
Helgenberger got the chance to act with her husband, Alan Rosenberg, again when he guest starred on CSI, Season 5 ("Weeping Willows") and Season 7 ("Leaving Las Vegas").