The actress, who plays Emily Prentiss, will exit the CBS drama at the conclusion of its current seventh season.
"After six wonderful years playing Emily Prentiss, I have decided it's time for me to move on," Brewster said in a statement to Deadline.
"As much as I will miss my Criminal Minds family, I am excited about the future and other opportunities."
The star apparently informed the Criminal Minds cast and crew of her decision yesterday (February 14).
"We were all sad to hear the news, but we respect and support any decision Paget wants to make," said showrunner Erica Messer. "Personally, I'm a huge fan and will continue to be one wherever she goes."
Brewster was previously dropped from Criminal Minds in 2010, along with co-star AJ Cook (Jennifer 'JJ' Jareau).
However, both were reinstated as series regulars for the current season. Brewster recently described her brief absence from the show as "dumb" and "a mess".
Criminal Minds continues tonight at 9/8c on CBS.
> Criminal Minds exec denies Mandy Patinkin return
Watch a promo for tonight's Criminal Minds below: