In the late 1950s, Weitzman's father, Seymour Weitzman, and his older brother Warren opened a shoe factory in Haverhill, Massachusetts, called "Seymour Shoes". Weitzman began designing shoes for his father's business in the early 1960s. Weitzman graduated from George W. Hewlett High School in 1958 and the Wharton School at the University of Pennsylvania in 1963. When Seymour died in 1965, Warren and Stuart ran the business. They sold the business to a company in Spain in 1971, and Weitzman continued to design shoes for the company. In 1994, he bought back the business, but he continues to manufacture his shoe designs in Spain.

Weitzman is known for providing one-of-a-kind, "million dollar" shoes to Oscar nominees to wear at the Academy Awards such as the pair of platinum sandals adorned with 464 diamonds that actress Laura Harring wore to the 2002 ceremony. For the 2007 Oscars, shoes were designed for and provided to Diablo Cody, who subsequently declined to wear them, stating that she was not aware of nor interested in the publicity attendant with wearing the shoes. Weitzman uses unique materials including cork, vinyl, lucite, wallpaper and 24-karat-gold. His shoes are sold in over 70 countries.

The eponymous company that Weitzman founded has changed hands a number of times. Jones Apparel Group purchased a majority stake in the company in 2010 and later bought the remaining 45 percent of shares retained by Weitzman in 2012. In January 2015, Sycamore Partners LLC (the private equity fund that owns Jones Apparel Group) agreed to sell the company to Coach, the luxury fashion house, for $574M. As part of the deal, Weitzman stayed on as a shoe designer for the company. In May 2017, Stuart Weitzman Holdings, LLC, appointed Giovanni Morelli as Creative Director and Weitzman stepped down from his role.