The actor - who has played The Doctor since 2010 - will leave the show after this year's Christmas special, the BBC has confirmed.
Smith, 30, said that it has been "an honour" to be a part of the long running series.
He said: "Doctor Who has been the most brilliant experience for me as an actor and a bloke, and that largely is down to the cast, crew and fans of the show.
"I'm incredibly grateful to all the cast and crew who work tirelessly every day, to realise all the elements of the show and deliver Doctor Who to the audience.
"Many of them have become good friends and I'm incredibly proud of what we have achieved over the last four years."
He continued to thank Steven Moffat for the "varied, funny, mind-bending and brilliant scripts" that have given him the "greatest and most rewarding challenges" of his career.
He said: "It's been a privilege and a treat to work with Steven, he's a good friend and will continue to shape a brilliant world for the Doctor.
"The fans of Doctor Who around the world are unlike any other; they dress up, shout louder, know more about the history of the show (and speculate more about the future of the show) in a way that I've never seen before, your dedication is truly remarkable.
"Thank you so very much for supporting my incarnation of the Time Lord, number Eleven, who I might add is not done yet, I'm back for the 50th anniversary and the Christmas special."
Moffat praised Smith for consistently "surprising" him whilst playing the eleventh incarnation of the Time Lord.
The executive producer added: "Whatever we threw at him - sometimes literally - his behaviour was always worthy of the Doctor.
"But great actors always know when it's time for the curtain call, so this Christmas prepare for your hearts to break, as we say goodbye to number Eleven. Thank you Matt - bow ties were never cooler.
"Of course, this isn't the end of the story, because now the search begins. Somewhere out there right now - all unknowing, just going about their business - is someone who's about to become the Doctor.
"A life is going to change, and Doctor Who will be born all over again. After 50 years, that's still so exciting."
Matt Smith will appear alongside David Tennant in the 50th anniversary special before his final episode at Christmas.
Companion Jenna Louise Coleman is to continue to appear alongside the new Doctor when the show returns in 2014.
Watch Matt Smith's first appearance as The Doctor below: