MacDowell dropped out of Winthrop College as a sophomore in 1978, and signed with Elite Model Management. She appeared in print and televion advertisements for the cosmetic and haircare company L'Oreal, a job she continued even after she got her first job as an actress. A series of television commercials for Calvin Klein drew attention to her and led in 1984 to her film debut in Greystoke - The Legend of Tarzan, Lord of the Apes, a role in which her lines were rerecorded by Glenn Close. In 1985, she had a small part in St. Elmo's Fire, but her film career seemed to have stalled.

Four years later, in 1989, she hit her professional stride. Director Steven Soderbergh cast her in the independent film Sex, Lies, and Videotape; her performance earned her several award nominations and led to a series of starring roles in films such as Green Card, The Object of Beauty, and Short Cuts. As of 2004, her biggest successes were in the box office hits Groundhog Day and Four Weddings and a Funeral.

MacDowell was married between 1986 and 1999 to former model and rancher Paul Qualley. The couple had a son and two daughters. She was married to Atlanta, Georgia businessman Rhett Hartzog from 2001 to 2004. In January 2006, she became engaged to businessman Kevin Geagan.