In 1998, Murphy was named VH1/Vogue’s Model of the Year. She played Dubbie in Barry Levinson’s film Liberty Heights. She was one of the “Modern Muses” on the November 1999 millennium cover of American Vogue and was chosen to represent Calvin Klein’s perfume, Contradiction. She was featured on the cover of the Sports Illustrated Swimsuit Issue in 2005 and 2006.

In 1999, Murphy married surf shop owner Jake Schroeder, whom she met while on vacation. She gave birth to their daughter, Dylan Blue, on December 28, 2000, and the three posed for Vogue. Murphy and Schroeder divorced in 2002. In 2006, Schroeder was charged with grand theft and extortion for trying to sell a sex tape the couple had made on their honeymoon; he pleaded guilty to grand theft and the extortion charges were dropped.

In July 2012, Murphy was hired to replace Angela Lindvall as host of Project Runway All Stars on Lifetime, after Rosie Huntington-Whiteley dropped out for a film project. In 2012, Murphy was ninth on the Forbes top-earning models list, estimated to have earned $3.5 million in one year.

As of 2015, Murphy and boyfriend Lincoln Pilcher practice Transcendental Meditation.