Smart was born in Topanga, California. Her mother, Judy Lysle (née Carrington), worked at a museum, and her father, John Boden Smart, was a salesman. Amy Smart studied ballet for ten years.
Smart married Carter Oosterhouse from HGTV on September 10, 2011, in Traverse City, Michigan.
While modelling in Italy, Smart met fellow model Ali Larter and the two "became instant friends", according to Larter. Whilst in Los Angeles, the two took acting classes together. After appearing in the video for The Lemonheads' 'It's About Time' in 1993, Smart's first film role was in director Martin Kunert's film Campfire Tales, followed by a small role as Queenie in the 1996 rendition of John Updike's short story, "A&P". She had a minor role in the 1997 film Starship Troopers as the co-pilot for (and friend of) Carmen Ibanez (Denise Richards). She had a starring role in the mini-series The 70s, playing a young woman from Ohio. In 1999, Smart played the girlfriend of a popular American football player (played by James Van Der Beek) in the film Varsity Blues, re-uniting her with Larter.
Smart played a recurring character on the series Felicity from 1999 to 2001 — Ruby, a former girlfriend of Scott Foley's character. She co-starred in the films Road Trip (2000), Rat Race (2001), Starsky & Hutch (2004), and The Butterfly Effect (2004). In 2005, Smart co-starred with Ryan Reynolds in the romantic comedy film Just Friends, which had a total domestic box office gross of $32,619,761, and a total worldwide box office of $50,817,598. In 2003, Smart also had a small role in the American sitcom Scrubs, playing Jamie Moyer (aka "Tasty Coma Wife"), one of main character J.D.'s love interests.
In 2005, Smart starred as Sarah in a British independent film called The Best Man. Seth Green was her co-star. She also appeared in the 2006 film Crank, portraying the girlfriend of the lead character, Chev Chelios (played by Jason Statham). She reprised the role in the sequel, Crank: High Voltage, released in 2009. Smart was a regular cast member in the short-lived 2006 CBS television series Smith. She also has voiced some of the characters in the animated series Robot Chicken, created by Seth Green. Smart appeared as Joy in the 2006 movie Peaceful Warrior, starring Scott Mechlowicz and Nick Nolte. She stars as Melissa in the 2008 independent film Seventh Moon. In 2011, Smart joined the Showtime drama/comedy Shameless as the recurring character Jasmine Hollander. She continues to guest star in season two, which began airing January 8, 2012.