The actor, known for his role as Dr. Alex Karev, last featured in the 350th episode of the show, which aired in the U.S. in November (19) as part of the current season 16, and he hasn't filmed any others since.
In a statement issued to Deadline, Chambers explained the reason for his departure, writing, "There's no good time to say goodbye to a show and character that's defined so much of my life for the past 15 years."
"For some time now, however, I have hoped to diversify my acting roles and career choices. And, as I turn 50 and am blessed with my remarkable, supportive wife and five wonderful children, now is that time."
Chambers went on to express his gratitude to "Grey's Anatomy" creator Shonda Rhimes, and the series' three remaining original co-stars.
"As I move on from 'Grey's Anatomy', I want to thank the ABC family, Shonda Rimes, original cast members Ellen Pompeo, Chandra Wilson and James Pickens Jr., and the rest of the amazing cast and crew, both past and present, and, of course, the fans for an extraordinary ride," he continued.
"Grey's Anatomy" debuted in 2005, and will continue for at least one more year after network bosses renewed the series for its 17th season, with leading lady Pompeo remaining attached to star.