In the early 1980s, MacDowell modeled for Vogue magazine and appeared in ad campaigns for Yves Saint Laurent, Vassarette, Armani perfume, Sabeth-Row, Mink International, Anne Klein and Bill Blass. She worked with such esteemed photographers as Bruce Weber, Richard Avedon, Helmut Newton, Irving Penn and Herb Ritts among others. A series of billboards in Time Square and national television commercials for Calvin Klein drew attention to her and led to her 1984 film debut in Greystoke: The Legend of Tarzan, Lord of the Apes, a role in which her lines were recorded by Glenn Close because her southern accent was too pronounced. In 1985, she had a small part in St. Elmo’s Fire, but her film career seemed to have stalled.

MacDowell used this time to study method acting with teachers from The Actors Studio in addition to working privately with the renowned coach Harold Guskin. Four years later, MacDowell hit her professional stride. Director Steven Soderbergh cast her in the 1989 independent film sex, lies, and videotape. Her performance earned her an Independent Spirit Award, a Los Angeles Film Critics Association Award for Best Actress, several other award nominations and led to a series of starring roles in films such as Green Card, The Object of Beauty, and Short Cuts.

In the 1990s, MacDowell achieved stardom due to the box office success of the 1993 comedy by Harold Ramis, Groundhog Day, and the 1994 global blockbuster, Four Weddings and a Funeral (FWAAF), opposite Hugh Grant. Groundhog Day and FWAAF remain MacDowell’s biggest box office hits to date.

MacDowell appears in print and television advertisements for the cosmetic and haircare company L’Oréal.