Jolie, 41, and Pitt, 52, married in 2014, eight years after establishing their relationship.
The news was broken by entertainment site TMZ, who said Jolie was filing for physical custody of their children and for Pitt to have visitation and joint legal custody.
The couple have six children together: Maddox, 15, Pax, 12, Zahara, 11, Shiloh, 10, and twins Knox and Vivienne, eight.
Laura Wasser, the celebrity lawyer who represented Johnny Depp in his divorce from Amber Heard, is reportedly representing Jolie. Wasser previously represented Jolie in her divorce from Billy Bob Thornton.
Jolie's lawyer Robert Offer said in a statement on Tuesday: “This decision was made for the health of the family. She will not be commenting, and asks that the family be given its privacy at this time."
The actors first met when they played married spies in Mr And Mrs Smith. Pitt was married to Friends star Jennifer Aniston and announced his divorce soon after.
They wed in a secret ceremony attended by close family friends at Château Miraval in the south of France, the wine estate that the couple purchased for $60 (£36m) in 2008.
Jolie wore a veil designed by her children. People and Hello! obtained exclusive rights to their wedding and Jolie told the magazine: “I wanted the kids to be a part of everything including the dress because that's our family; that represents the way we live our life together.”
The date of separation is listed as 15 September. TMZ, which claims to have seen a legal filing, said Jolie “was extremely upset” by Pitt's parenting methods.
Representatives for Pitt and Jolie did not immediately respond to a request for comment.
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