Margulies, the youngest of three daughters, was born in Spring Valley, New York, the daughter of Francesca, a ballet dancer and eurythmy teacher, and Paul Margulies, a writer who wrote the Alka-Seltzer catch phrase "Plop, Plop, Fizz, Fizz, oh what a relief it is". Margulies attended Green Meadow Waldorf School. As a child, she lived in New York, France, and England. Margulies's parents are Jewish, Read more...

Her first movie role was as a prostitute looking to go straight in the Steven Seagal film Out for Justice. In 1994, Margulies was cast in a role in the pilot episode of ER as a character who, despondent over her relationship with George Clooney's character, Doug Ross, attempted suicide. Her character was originally supposed to die due to the suicide attempt, however, the producers changed the plot Read more...

Margulies and her husband Keith Lieberthal were married on November 10, 2007 in Lenox, Massachusetts. Their son Kieran Lindsay Lieberthal was born on January 17, 2008.