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Born in New Orleans and raised in Tennessee, she began her career as a child actress, making her professional screen debut in The Man in the Moon (1991), for which she was nominated for a Young Artist Award.
Following breakout roles in Desperate Choices: To Save My Child (1992) and Jack the Bear (1993), she starred in the comedy-drama Pleasantville (1998), for which she won the Young Hollywood Award for Breakthrough Performance.
She received a star on the Hollywood Walk of Fame in 2010.
Witherspoon was raised as an Episcopalian, and has said she is proud of the "definitive Southern upbringing" which she received.
The film and Witherspoon's portrayal of Sharp received mixed reviews, as The Hollywood Reporter wrote, "Nair's cast is splendid.
Witherspoon does justice to the juicy role by giving the part more buoyancy than naughtiness." At the same time, The Charlotte Observer called her work "an excellent performance that's soft around the edges" and the Los Angeles Times concluded that Becky is "a role Reese Witherspoon was born to play".
In 2003, Witherspoon followed up the success of Legally Blonde by starring in the sequel Legally Blonde 2: Red, White & Blonde.
However, LA Weekly wrote "[Witherspoon] ends up conveying so little of what’s at once appalling and perversely attractive about the would-be mistress of Vanity Fair" and states that it may have to do with Witherspoon's vanity, "with an Oscar-less young star’s need to be loved more than anyone could conceivably love the “real” Becky Sharp.".
In late 2004, Witherspoon began working alongside Mark Ruffalo on the romantic comedy Just Like Heaven.
In 2014, Witherspoon produced the thriller Gone Girl and received critical acclaim for portraying Cheryl Strayed in Wild, for which she earned her second Academy Award nomination for Best Actress and a fourth Golden Globe nomination.
In 2017, she produced and starred in the HBO drama series Big Little Lies, for which she received two Primetime Emmy Award nominations for Outstanding Lead Actress in a Miniseries or a Movie and Outstanding Limited Series, winning the latter as a producer.