O'Toole was born in Houston, the daughter of Dorothy Geraldine (née Niland) and William West Toole Jr.

[5] In 1981, she starred in the HBO onstage production of Vanities, as well as in the TV movie Stand By Your Man, which detailed the life of country music legend Tammy Wynette.

Also in 1985, she had a starring role as Ms. Edmunds in the original Bridge to Terabithia, and appeared in the TV adaptation of Strong Medicine the following year.

In 1995, she starred as Cheryl Keeton in the 1995 Lifetime television film based on Ann Rule's true crime novel Dead by Sunset.

[11] She had a recurring role on the television show Nash Bridges (1996)[12] and starred in her own series The Huntress (2000) as a female bounty hunter.

[14] In 2010, O'Toole played the role of Veronica, a middle-aged woman with a severe case of Alzheimer's, in the television series Lie to Me.

[24] In 2007, O'Toole appeared as a backing singer for her husband's fictional band Spinal Tap at the London leg of the Live Earth concerts.

She has also performed on the band's 2009 Unwigged and Unplugged tour, and contributed lyrics to "Short and Sweet" on the 2009 Spinal Tap album Back from the Dead.

[citation needed] In 2011 she starred in CAP21's production of the new musical Southern Comfort, based on the Sundance award-winning documentary, by Dan Collins and Julianne Wick Davis.

[25][26] O'Toole met fellow actor Michael McKean while working together on the 1998 television movie Final Justice.