Nichols was born in the Rogers Park neighborhood of Chicago, Illinois, to a father of Romanian and Hungarian descent and a Texan mother of Spanish and Mexican ancestry.She was raised in Naperville, Illinois. She is the oldest of three siblings, having two younger brothers. A rebellious teenager, Marisol Nichols stated in an interview with AskMen.com, "I remember being 17 and looking around at some of the people that I was hanging out with, and I had this realization that if I didnt knock this off now it would become my life", and replaced her rebellious behavior with more productive activities like acting.

In 1996, she appeared in episodes of Due South and Beverly Hills, 90210. In 1997 she made her movie debut in the film Vegas Vacation with Chevy Chase. She also had supporting roles in the films Scream 2, Friends 'Til the End, Can't Hardly Wait, Jane Austen's Mafia and The Sex Monster.

From 2000 to 2002, she starred in the Showtime drama series Resurrection Blvd.. In 2003, she made guest appearances on episodes of Friends, CSI: Crime Scene Investigation, Law & Order: Special Victims Unit, Nip/Tuck and Charmed. In 2006, she appeared in six episodes of Cold Case and starred in the film Big Momma's House 2. She starred in the short-lived TV series Blind Justice in 2005 and In Justice, in 2006. In 2007, she starred in 24 as Special Agent Nadia Yassir. In 2008, she starred in the film Felon with Stephen Dorff.

In 2010, Nichols portrayed Sarah Monahan in the short-lived supernatural crime drama The Gates, a summer series on ABC.

She also was a guest star in an episode NCIS: Los Angeles in 2010, as Tracy Keller, former partner and potential romantic interest for Special Agent G. Callen (Chris O'Donnell). Nichols's character will appear in the sixth episode of Season 2. She also had a cameo in Kristin Chenoweth's music video for I Want Somebody (Bitch About).

Nichols, a Scientologist, is an active advocate of Criminon and the Citizens Commission on Human Rights. She became a member of Church of Scientology when she was introduced to it by her chiropractor. She has been married to actor Taron Lexton since 13 April 2008, and their child, Rain India Lexton, was born 30 September 2008.

She currently resides in Los Angeles, California.

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