Smith, who joined the cast in 2010 as the show's 11th Time Lord, will make his final appearance in the 2013 Christmas special, the BBC said.
"It's been an honor to play this part, to follow the legacy of brilliant actors, and helm the Tardis for a spell with 'the ginger, the nose and the impossible one.' But when ya gotta go, ya gotta go," Smith said, referencing his co-stars, Karen Gillan, Arthur Darvill and Jenna-Louise Coleman.
Smith said he was "incredibly proud" of his work with on the show.
Writer and executive producer Steven Moffat said: "Every day, on every episode, in every set of rushes, Matt Smith surprised me. The way he'd turn a line, or spin on his heels, or make something funny, or out of nowhere make me cry -- I just never knew what was coming next.
"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 11. Thank you Matt -- bow ties were never cooler," Moffat said.
In November, "Doctor Who" will celebrate its 50th anniversary, the BBC said. Smith has already filmed an episode to mark the occasion.