Smith was revealed as the Eleventh Doctor in the British science-fiction television series Doctor Who in January 2009 to replace David Tennant, who announced his departure in October 2008. Smith was a relatively unknown actor compared to the actors then speculated about possibly taking on the role, who included Paterson Joseph, David Morrissey, Sean Pertwee, James Nesbitt, Russell Tovey, Catherine Zeta-Jones, Chiwetel Ejiofor, Robert Carlyle, and Billie Piper. Smith was first named as a possible successor less than a day before he was announced as the Eleventh Doctor, on an edition of 3 January 2009 of BBC Breakfast, among the names speculated about. His obscurity prompted the news headline "Doctor Who?", a riff on the show's title.
Smith was one of the earliest actors to audition for the role, performing on the first day. The production team, consisting of the incoming producer, Steven Moffat, and BBC Wales Head of Drama and executive producer, Piers Wenger, immediately singled him out based on his performance. Smith additionally auditioned for the role of John Watson in the Moffat-created Sherlock, undergoing auditions at the same time; he was unsuccessful, as Moffat believed his eccentric acting style was closer to Holmes, whose role had already been given to Benedict Cumberbatch. At 26 years old, Smith was three years younger than Peter Davison was at the time of his casting as the Doctor in 1981, and younger than any other actor suggested for the role. After three weeks of auditions, Moffat and Wenger agreed that it had "always been Matt" and approached him to accept the role.
The BBC were cautious about casting him because they felt that a 26-year-old could not play the Doctor adequately; Wenger shared the same sentiment but thought Smith had proven his acting quality in Party Animals, which Wenger thought highlighted Smith's "mercurial qualities". Some fans of the show believed that Smith was inexperienced and too young for the role, while others supported him by citing his demonstrated acting ability. For his performance in his first series, he was nominated in the Outstanding Drama Performance Category of the National Television Awards. Smith is the first Doctor to be nominated for a BAFTA for Best Actor.
Smith has said of his character: "The Doctor is excited and fascinated by the tiniest of things. By everything. By every single thing. That's what's wonderful about him as a character. It's why children like him, I think. Because he doesn't dismiss anything. He's not cynical. He's open to every single facet of the universe." In June 2010, Smith appeared on stage with Orbital, and performed with them a version of the Doctor Who theme, at the Glastonbury Festival. Smith hosted the Doctor Who Prom at the Royal Albert Hall on 24–25 July 2010. On the morning of 26 May 2012, Smith carried the Olympic torch in Cardiff, an activity which was noted by Doctor Who fans for its resemblance to a 2006 episode of the show in which the Doctor carried the torch. On 1 June 2013, the BBC announced that Smith would be leaving Doctor Who at the end of the 2013 Christmas special. Upon reflecting on his decision to leave in a 2016 interview, Smith expressed regret for not staying longer, owing to wanting to work longer with co-star Jenna Coleman. In 2018, while appearing on Desert Island Discs, Smith revealed that he nearly turned down the role of the Doctor. He was succeeded in 2013 by Peter Capaldi.