She has worked with several well-known photographers, including Herb Ritts, Richard Avedon, and Gilles Bensimon. In 1991 and 1994 she appeared in Playboy magazine.

She started her modeling career, by working for local newspapers and department stores in her hometown, at the age of 14. A year later she won the Elite Model Management Look of the Year model contest. 5'10" Stephanie is noted for her long, graceful legs in modeling swimwear, lingerie, hosiery, sleepwear, and clothing.

In the latter 1980s and earlier 1990s, Seymour appeared in numerous issues of the Sports Illustrated swimsuit edition. Also, in the latter 1980s and earlier 1990s, Seymour was a primary lingerie and hosiery model for the relatively new Victoria's Secret company in its mail-order catalogs and retail stores. She and Dutch model Frederique helped Victoria's Secret grow from a new company to one of the world's giants in women's lingerie, hosiery, swimwear, and clothing.

From 1989 to 1990 she was married to guitarist Tommy Andrews. The marriage failed, but resulted in the birth of Dylan Thomas Andrews in 1991.

After that she became associated with Axl Rose, the lead singer of Guns N' Roses. She appeared in two music videos of Guns N' Roses: "Don't Cry" and "November Rain". Their tumultuous relationship ended in 1993.

In 1994 she married the media mogul Peter Brant. In 1993 she gave birth to Peter Brant, Jr.; in 1997 to Harry Brant; and in 2004 to Lilly Margaret.

In 1998 her book Stephanie Seymour's Beauty Secrets for Dummies was published.

In 2000 she played Helen Frankenthaler in the movie Pollock.

In 2002 she was Sara Lindstrom in the "Crazy" episode of Law & Order: Criminal Intent.