The presenter, who took over the show in January 2007, said he is leaving so he can return to working on "entertainment-based shows".
"It's been wonderful hosting a programme which is part of TV folklore," the 76-year-old told The Sun.
"I've made a lot of new friends. Carol Vorderman has been a joy... It's been a giggle since day one."
He continued: "But I miss the thrill of stepping out on a live stage for the one-man concerts and the challenge of live TV entertainment-based shows."
O'Connor's last show will air in November.
Channel 4's head of daytime Helen Warner said: "We are very sorry to see Des leave.
"He has done a fantastic job hosting Countdown, bringing warmth and humour to the role, as well as the benefit of his many years in the business."
Previous Countdown hosts include Richard Whiteley and Des Lynam.