Harmon was born in Highland Park, Texas, to Lawrence Paul Harmon (who worked in a Dallas hospital information network) and Daphne Demar Caravageli. Her mother is of Greek descent and her father is of German and Native American ancestry. Her parents divorced in 1982 and her father later re-married.

Harmon worked as a child model and in 1988, won a Seventeen modeling contest. She attended Highland Park High School until 1990 and won a Spectrum Model Search contest shortly afterward, subsequently pursuing a successful modeling career and becoming well known in the early 1990s. She worked as a runway model for Calvin Klein, Giorgio Armani, and Donna Karan and appeared on the covers of ELLE, Cosmopolitan, and Esquire. She is signed to IMG Models in New York City.

Harmon began acting in 1995 after being discovered on a plane by David Hasselhoff. She then starred in several television series, including Baywatch Nights, Baywatch and C-16: FBI; she also appeared in the 1998 film, Lawn Dogs, which received only a limited theatrical release. In the early 2000s, Harmon became better known as playing Abbie Carmichael on the series Law & Order, a role she played from 1998 to 2001. During this time, she also voiced Barbara Gordon in the animated film, Batman Beyond: Return of the Joker, replacing Stockard Channing, as well as appearing on Law & Order.

Harmon left Law & Order to concentrate on her film career, saying that she preferred working in film than television. After appearing in the 2001 direct-to-video film Good Advice, she had a major role in Agent Cody Banks, playing the CIA handler of a teenage agent (Frankie Muniz). The film opened in March 2003 and became a minor hit, grossing $47 million. Although Harmon was originally scheduled to appear in the sequel, the producers chose to take a more comedic approach, and replaced Harmon with Anthony Anderson. In 2006, Harmon co-starred with Cuba Gooding Jr. and James Woods in the direct-to-DVD political suspense drama End Game.

In 2006, Harmon starred as the lead in the ABC pilot Secrets of a Small Town. Despite testing highly with focus groups, the pilot was not picked up by ABC due to its high budget. She also starred in another failed television show on NBC, Inconceivable. The program was canceled after two episodes.

In 2007, she starred in another ABC pilot, Women's Murder Club, a police drama which was picked up by ABC.

Harmon married to former professional football player Jason Sehorn. The two were engaged on March 13, 2000. Harmon was taping an interview segment on the Tonight Show with Jay Leno when Leno called Sehorn out as a surprise guest. Sehorn immediately walked up to where Angie was sitting, and knelt down on one knee in front of her chair and proposed. (She thought that he was in New York at the time.) They were married on June 9, 2001 and have two daughters: Finley Faith (born October 14, 2003 in Dallas, Texas) and Avery Grace (born June 22, 2005 in Dallas, Texas). On August 20, 2008, Harmon and Sehorn announced that they are expecting their third child.

She is left-handed.