In the early 1980s she 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. In the May 1982 issue of GQ she appeared in a Bruce Weber layout with cover model Jeff Aquilon. A series of 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 at Cannes Film Festival, 2001
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.