She started her modeling career 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. Standing 5'10", Seymour is noted for her long, graceful legs in modeling swimwear, lingerie, hosiery, sleepwear, and clothing.

In the late 1980s and early 1990s, Seymour appeared in numerous issues of the Sports Illustrated swimsuit edition, including once on the cover of the magazine. During the same period, 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.

In 1998 her book Stephanie Seymour's Beauty Secrets for Dummies was published. In 2006 she posed partially nude for Germany's MAX magazine. Also in 2006 she did a photo shoot for Gap with her family.

In July 2007, it was reported that Salvatore Ferragamo had finished the creative campaign for his fall/winter 2007/2008 collection featuring Seymour and Claudia Schiffer. The collection was shot on location in Italy with Mario Testino. In the promotional photos, the supermodels play film stars protected by bodyguards and pursued by the paparazzi. The ads are slated to debut in key fashion and lifestyle books starting in August.