The 41-year-old Jolie filed legal documents on Monday citing irreconcilable differences with Pitt, 52, and listing their date of separation as September 15, according to entertainment news websites TMZ and People.
“This decision was made for the health of the family,” Jolie’s attorney Robert Offer said in a statement circulated to US media.
“She will not be commenting at this time, and asks that the family be given their privacy during this difficult time.”
Two of the world’s biggest stars, Pitt and Jolie formed a Hollywood power couple second to none, so famous they were known simply by their combined first names.
The A-listers wed in France in August two years ago, but have been a couple since 2004 and have six children together, three of whom are adopted.
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Jolie is seeking physical custody of the children, with visiting rights for Pitt, according to TMZ, which said she was not seeking spousal support.
The couple was last seen together in public in mid July, just ahead of their second wedding anniversary.
Pitt came into the public eye 25 years ago with a much-talked-about shirtless debut as eye-candy in the hit movie “Thelma and Louise” — and went on to become a household name in Hollywood.
A three-time Oscar nominee for his acting, Pitt took home a golden statuette for best picture in 2014 as a producer of “12 Years A Slave.”
He has built a resume of varied film roles, starring alongside some of the industry’s other mega-watt stars: with Tom Cruise in “Interview with a Vampire,” Anthony Hopkins in “Legends of the Fall” and George Clooney in “Ocean’s Eleven.”
Jolie catapulted to stardom with her role in 1999’s “Girl, Interrupted,” taking home an Academy Award for best supporting actress for her fierce portrayal of a rebellious woman in a mental institution.
She has since played everything from a fairy tale villain (“Maleficent”) to a sexy video game heroine (“Lara Croft: Tomb Raider”) to the widow of assassinated American journalist Daniel Pearl (“A Mighty Heart”).
The red carpet darling is now better known for her humanitarian work than for her tabloid-ready actions, having served for several years as a goodwill ambassador for the United Nations High Commissioner for Refugees.
More recently, she has been a vocal advocate for victims of sexual violence in war zones, co-hosting a global summit on conflict rape in 2014 in London.
One of the world’s most visible symbols in the battle against cancer, she underwent a double mastectomy and removal of her ovaries and fallopian tubes to prevent an aggressive form of the disease that killed her mother, grandmother and aunt.
Jolie had been married twice before, to actors Jonny Lee Miller and Billy Bob Thornton.
News of her third divorce spread quickly on social media, with #brangelina the top trending hashtag on Twitter.
Many users posted memes featuring former “Friends” star Jennifer Aniston — Pitt’s previous wife — including one of her on the phone saying: “And that, my friend, is what they call closure.”
Pitt, born to a middle-class family in Oklahoma, studied journalism and advertising before heading West to Hollywood where he supported himself at first with part-time jobs, including as a chauffeur, removal man and even dressing up in a chicken suit to advertise a fast-food chain.
But from 1987 the work started to trickle in, with bit parts in the television series “Dallas” and “21 Jump Street” and a few low-budget movies.
His position as a Hollywood golden boy was assured by his 2000 marriage to Aniston, which made them one of the hottest couples in the world.
Pitt and Jolie fell in love four years later on the set of action film “Mr & Mrs Smith,” although they didn’t get engaged until 2012.
In May 2006 Jolie gave birth to their first child, a girl named Shiloh.
“Because of the film, we ended up being brought together to do all these crazy things, and I think we found this strange friendship and partnership that kind of just suddenly happened,” Jolie Pitt told Vogue in 2006.
Their joint fortune is estimated at over $300 million, and they are among the highest paid stars in Hollywood.
Jolie, the daughter of Oscar winner Jon Voight, made her directorial debut in 2011 with “In the Land of Blood and Honey,” an unflinching drama about rape as a weapon in wartime Bosnia.
Her fourth feature behind the camera, historical thriller “First They Killed My Father,” is being released on Netflix later in the year.
— Benazir Mir Samad (@BenazirMirSamad) September 20, 2016
If a couple with millions of dollars, six kids and a brand of overpriced rose wine can’t make it, we should all just give up now #brangelina
— Joanna Hausmann (@Joannahausmann) September 20, 2016
— Lauren Luxford (@LNLux) September 20, 2016
— E4 (@E4Tweets) September 20, 2016
— aimee (@halelovatos) September 20, 2016