Baker made his first appearance in Doctor Who as Commander Maxil in the story Arc of Infinity (1983). Producer John Nathan-Turner described Baker's performance as being "quite arch" and a little sassy[citation needed]. Maxil was one of the few characters actually to shoot the Doctor, then played by Peter Davison.

At the time of Baker's casting as Davison's successor he was the only actor portraying the Doctor to have appeared in the television series as another character prior to taking on the leading role (in 2013 Peter Capaldi was announced as the Twelfth Doctor after having previously appeared in another role in the 2008 episode "The Fires of Pompeii"). When Baker was cast to replace Davison, many fans cited that shooting scene in Arc of Infinity, prompting Baker to say jokingly that he got the part of the Doctor by killing the incumbent. Colin is no relation to Tom Baker, who played the Fourth Doctor previously in Doctor Who.

Baker's first appearance as the Doctor occurred at the final minutes of The Caves of Androzani, where he delivered his first few lines. The closing title sequence for episode four features Baker's face instead of Peter Davison and credits him as the Doctor before Davison's own credit. This was the first (and, to date, only) time that the new lead received top billing in the final story of an outgoing Doctor. Baker then made his first full story debut the following week in The Twin Dilemma. It was the first time since 1966, and only the second time in the series' history, that a new leading actor's debut story was shown before the conclusion of the previous lead's season.

Baker's era was interrupted by an 18-month hiatus which was announced in February 1985, mid-way through transmission of his first full season. One new Doctor Who story, Slipback, was made on radio during the hiatus. The Controller of BBC1 at the time, Michael Grade, criticized Doctor Who, saying that the program had become overly violent, with farcical storylines during season 22 in 1985. The program returned for its 23rd season in September 1986. Season 23 featured a reduction in episodes produced, and the 14-episode-long serial The Trial of a Time Lord. This serial was a meta-textual reference to the fact that the series itself was "on trial" at this time.

In 1986, Baker told an interviewer, "Tom Baker did it for seven years. ... There's a part of me which likes to have a tilt at records. I would like to think that maybe I'd still be doing it in eight years' time." Later that year Baker was dismissed from the part at the insistence of BBC management, who wanted to refresh the show. Michael Grade allegedly disliked Baker's performance and BBC Head of Series Jonathan Powell has since said that the BBC was looking for "one last chance saloon, for an actor who would take off with the public." He was removed from the part after starring in only eleven stories and just short of three years in the part, including the hiatus, making his tenure as the Doctor the shortest at that point. After his sacking Baker refused to return to film a regeneration sequence, meaning that his replacement Sylvester McCoy played the fatally injured Sixth Doctor in a blonde wig as he regenerates in the opening minutes of Time and the Rani, his face hidden by visual-effects blurring as the regeneration process occurs.

On 4 September 2011 at Riverside Studios, Hammersmith, London, Baker accepted the presidency of 'The Doctor Who Appreciation Society' following Jon Pertwee and then Nicholas Courtney in the role. Baker was elected following an online poll of the society's members where he won more votes than all the other candidates combined.