Angelina's lawyer confirmed the split to BBC News.
Her attorney revealed that Angelina, 41, was the one to initiate the separation and filed for divorce on 19 September, stating that she had made the decision for "the health of the family."
The brief statement said: "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 couple are parents to six children: sons Maddox, Pax and Knox, and daughters Zahara, Shiloh and Vivienne.
According to TMZ, the divorce papers cite irreconcilable differences and the US website alleges Angelina has requested custody of the kids, allowing Brad visitation rights.
Brad's lawyer has yet to comment.
This is the second divorce for Brad, who was previously wed to Jennifer Aniston. Angelina has been divorced twice following marriages to actors Johnny Lee Miller and Billy Bob Thornton.
Angelina and Brad, 52, famously began dating back in 2004 after filming Mr and Mrs Smith - where Brad previously said he "fell in love" with Angelina on set. It made headlines as Brad was married to Jennifer at the time of filming the action comedy about a married couple who learn they're both secret assassins.
Brad later split from Friends actress Jennifer and a few months later was pictured with Angelina and her son Maddox on a beach in Kenya. They confirmed their relationship shortly after.
Angelina went on to adopt daughter Zahara and son Pax, as well as giving birth to Brad's biological daughter Shiloh and their twins Vivienne and Knox.
The couple became engaged in 2012 but famously declared they wouldn't marry until same sex marriage was legal in California.
In August 2014 they tied the knot at their private estate in France, with all six children involved in the ceremony. Angelina memorably wore a wedding dress decorated with pictures drawn by the kids.
Just last year, the Hollywood couple worked together on the romantic drama movie By The Sea, written and directed by Angelina and co-starring both Angelina and Brad.