Harris was born in Worthington, Ohio. She graduated from Worthington High School (renamed Thomas Worthington High School). She went on to graduate from Otterbein College, in 1989, majoring in theatre.

Harris performed with the Los Angeles, California, improvisational comedy troupe the Groundlings, and taught for a time with the Groundlings school. She debuted on television in a 1993 episode of SeaQuest DSV.

After an appearance on Star Trek: Voyager in 1997, Harris went on to a recurring role in The WB's Sister, Sister. Other television credits include a stint as a correspondent for The Daily Show's 2002-2003 season, as well as roles on The Sarah Silverman Program, Reno 911!, The West Wing, Friends, Curb Your Enthusiasm, Monk, and, in November 2008, Desperate Housewives.

Harris played the supporting role of Kevyn Shecket, Kirstie Alley's personal makeup artist, on the Showtime series Fat Actress in 2005. She played Cooper in the ABC sitcom Notes from the Underbelly.

Her film credits include roles in Best in Show, A Mighty Wind, For Your Consideration, Starsky & Hutch, Kicking & Screaming, and Daddy Day Care. In the 2009 comedy The Hangover she plays Melissa, girlfriend to Ed Helms. She previously co-starred with Helms on the Daily Show. In 2010, she played Greg's mom in the film Diary of a Wimpy Kid.

Harris hosted Smoking Gun TV in 2004, and has made multiple appearances on such VH1 documentaries as I Love the '80s, I Love the '90s, and Best Week Ever.

Harris' TV commercial work includes ads for Dinty Moore, Avis, Expedia, Quaker Oats, T-Mobile, Geico, and a Super Bowl commercial for the 2010 Census. She is the voice of turtle Karolyn Slowsky in the Comcast Slowskys television commercials.

Harris has signed on to ABC's Cougar Town, TVGuide.com has confirmed. She will play Shanna, a woman that the network describes as being the "nemesis" of Jules.