The actress, who plays Dr Gregory House's on-off love interest Dr Lisa Cuddy, confirmed that she has declined to extend her contract due to a desire to pursue other opportunities.
"After much consideration, I am moving onward with a combination of disappointment at leaving behind a character I have loved playing for seven years and excitement of the new opportunities in acting and producing that lie ahead," Edelstein said in a statement.
The 44-year-old later tweeted: "Twitter friends, I am reading all your kind thoughts and it feels great to have such support. You are the best!"
The actress suggested in March that she was looking forward to returning for the new season along with the show's other cast members.
Following the news of Edelstein's departure, as well as confirmation that Hugh Laurie, Olivia Wilde, Peter Jacobson, Robert Sean Leonard and Omar Epps have all signed new contracts, only Jesse Spencer's status is unknown.
Laurie recently suggested that the eighth season of House could also be its last.
House airs on Mondays at 8/7c on Fox in the US and on Thursdays at 10pm on Sky1 in the UK.