Andie MacDowell was born in Gaffney, South Carolina, the daughter of Pauline "Paula" Johnston (née Oswald), a music teacher, and Marion St. Pierre MacDowell, a lumber executive. She is of part Scottish descent. Her family owned an Antebellum period summer house in Arden, North Carolina, which has since been made into a bed-and-breakfast named the Blake House Inn. Graffiti from her childhood visits are preserved in an upstairs bedroom closet. She attended Winthrop College for two years before moving briefly to Columbia, South Carolina. She was initially spotted by a rep from Wilhelmina Models while on a trip to Los Angeles before she would later sign with Elite Model Management in New York City in 1978.
In the early 1980s, MacDowell modelled for Vogue magazine and appeared in ad campaigns for Yves Saint Laurent, Vassarette, Armani perfume, Sabeth-Row, Mink International, Anne Klein and Bill Blass. A series of billboards in Times 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 dubbed by Glenn Close because her Southern accent was too pronounced for her to play the role of an Englishwoman. In 1985, she had a small part in St. Elmo's Fire.
MacDowell studied method acting with teachers from the Actors Studio, in addition to working privately with the renowned coach Harold Guskin. Four years later, director Steven Soderbergh cast her in the independent film Sex, Lies, and Videotape (1989). 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 director Harold Ramis's 1993 comedy, Groundhog Day, and Four Weddings and a Funeral (1994), opposite Hugh Grant.
Since 1986, MacDowell has appeared in print and television advertisements for the cosmetic and haircare company L'Oréal. In later years she has acted primarily on television and in independent films. In 2012 she co-starred in the short-lived ABC Family series Jane by Design.
MacDowell was married from 1986 to 1999 to fellow former model and rancher Paul Qualley, whom she met while both were posing for Gap ads. The couple have a son, Justin (born 1986), and two daughters, Rainey (born 1989, Miss Golden Globe 2012) and Sarah Margaret Qualley (born 1995), an actress. She was married to businessman Rhett Hartzog from 10 November 2001 to October 2004.