Richardson-Whitfield was born in Chicago, Illinois, the daughter of an African American-Native American mother and a white father, of Italian and English descent. She has three brothers: Josh Richardson, Chad Richardson, and Nalin. Richardson played tennis in high school, and launched her acting career in the Kuumba Workshop theater there. She graduated from the University of Chicago Laboratory Schools in 1985.

Richardson began her acting career in the theater before roles in television and film. In film, she played small roles in Prelude to a Kiss, Mo' Money, Posse, and later had major roles in Sioux City and A Low Down Dirty Shame. From 1994 to 1996 she had voice role of Elisa Maza on the animated series Gargoyles. She had many guest-starring roles in numerous television shows, such as Star Trek: Deep Space Nine, New York Undercover, The Pretender, Stargate SG-1, NYPD Blue, House, Bones, Criminal Minds, NCIS and Castle.

Richardson starred opposite Dixie Carter and Kathleen Quinlan in the CBS legal drama series, Family Law, from 1999 to 2002. She had recurring roles as Nancy Adams on Rude Awakening, and as Laura on CSI: Miami. She starred opposite Denzel Washington in the 2002 drama film Antwone Fisher. She also appeared in the 2004 horror film Anacondas: The Hunt for the Blood Orchid and starred opposite Will Smith in 2007's post-apocalyptic film I Am Legend. She later had a leading role in the independent dramas Pastor Brown (2009) and I Will Follow (2010). She also starred in The Sin Seer with Isaiah Washington, set for 2015 release.

On September 8, 2002, she married long-time boyfriend and fellow actor Dondre Whitfield. She and Whitfield have one daughter, Parker Richardson-Whitfield, and one son, Dondre Terrell Whitfield Jr. (born January 24, 2009). Whitfield has appeared along with her husband Dondre Whitfield in a late night infomercial as part of an advertising campaign to promote the Time Life Zestify Midnight Soul collection.

From 2006 to 2012, Richardson starred as Department of Defense agent (and later head of Global Dynamics) Allison Blake in the Syfy comedy-drama series Eureka. Her second pregnancy was written into the storyline of the series. After the series' cancellation, she was cast as the lead in the Lifetime drama pilot The Secret Lives of Wives. In 2014, Richardson was cast in a recurring role on Lifetime's The Lottery as the first lady of the United States, but she lost it to Shelley Conn; She also has a role on BET's Being Mary Jane as an old friend of the lead character. In 2015, Richardson was cast in the ABC Family series, Stitchers. In August–September 2016, she made appearances as one of the co-hosts of the Hollywood Today Live daily show seating next to Ross Mathews.

Richardson has also worked as a Director of episodic television. Following her directorial debut on two episodes of Ava DuVernay's original drama series for OWN, Queen Sugar (on which her husband Dondre Whitfield appears as a series regular), in 2016, Richardson has also directed an episode of the historical action-drama Underground for WGN America. In 2017, she directed two episodes of BET drama Rebel, and Shonda Rhimes' Scandal. In 2018, she also directed the 16th episode of Agents of S.H.I.E.L.D.'s season 5 entitled "Inside voices".