Duffy was born in New York City, the daughter of Carol, a homemaker, and Phil, a developer. She attended Park Ridge High School in Park Ridge, New Jersey, graduating in 1979. She received a bachelor's degree in recreational therapy from the University of Colorado at Boulder.
By 1989, Duffy was modeling and appearing in television commercials. She was a VJ for MTV in the early 1990s, under the name "Duff." She had small roles in a handful of films including Dumb and Dumber, and by 1995 was working as a correspondent for documentary filmmaker Michael Moore on his television shows TV Nation and The Awful Truth. While she was a Revlon “Charlie Girl” as well as the face of Almay Cosmetics. She also appeared in the 1994 film Blank Check.
In 1995, Duffy was diagnosed with a rare form of the disease sarcoidosis called neurosarcoidosis. Her brain and spinal cord were affected, leaving her partially paralyzed. She wrote about her affliction in the humorous 2000 autobiography Model Patient: My Life as an Incurable Wise-Ass.
She married John Lambros in 1997. They have one son, Jack "Lefty" Lambros.
In 2006, Duffy hosted House of Tiny Terrors on TLC. On July 7, 2007, she appeared on the Live Earth telecast on the Bravo Channel as a co-host at Giants Stadium, East Rutherford, New Jersey.
In 2008, Duffy began working with New York City's NYCTV on a series of emergency preparedness videos. The videos, which mimic the style of the network TV show Secrets of New York, help raise awareness of the perils of natural disasters and preventative actions families should take to prepare for them.
