Detective Murdoch is assisted by the three other main characters: Inspector Brackenreid (Thomas Craig), Doctor Julia Ogden (Hélène Joy), and the inexperienced but eager Constable George Crabtree (Jonny Harris), who aspires to be a mystery novel writer.

Albert Choi (Paul Sun-Hyung Lee formerly Appa in Kim's Convenience) replaces him as Inspector at Station House No 4, thereby becoming Murdoch's boss.

[5][6] Real history is an important element in most episodes, and the plots, though fictitious, sometimes involve real people, such as Buffalo Bill Cody, Annie Oakley, H. G. Wells, Nikola Tesla, Wilfrid Laurier, Jack London, Arthur Conan Doyle, Queen Victoria, Theodore Roosevelt, Oliver Mowat, Orville and Wilbur Wright, Henry Ford, Sir Winston Churchill, Bat Masterson, Alexander Graham Bell, Emma Goldman, H. P. Lovecraft, Harry Houdini, Thomas Edison, Lucy Maud Montgomery and Helen Keller.

In Season 12 Frank Lloyd Wright appears as the architect that Murdoch and Ogden hire to design their customized home, dubbed the Murdoch Mystery Mansion which incorporates many of the stylistic touches such as an Open Concept layout without doors or walls separating rooms, a low flat roof and stained glass windows with geometric designs evoking nature that Wright was known for.

Another underlying theme of the series involves the fact that Murdoch is a Catholic in what was at the time a predominantly Protestant city and the prejudices that he occasionally encounters as a result.

[12] The program was well received, both by the audience and by the critics: in the summer of 2008, it was nominated for 14 Gemini Awards by the Academy of Canadian Cinema and Television.

[16] One big fan of the show was Canadian Prime Minister Stephen Harper, who agreed to play a small role in one of that season's episodes.

[17] The episode in which he appeared, playing a "clueless cop who fails to recognize then prime minister Wilfrid Laurier", aired in late July 2011.

[23] Noted examples have included Stephen Harper, at the time the Prime Minister of Canada, in a small role as a police desk clerk;[23] William Shatner portraying writer Mark Twain;[24] a special Christmas episode which included appearances by Ed Asner, Brendan Coyle, Kelly Rowan and television news anchor Peter Mansbridge;[25] an episode which featured David Onley, the Lieutenant Governor of Ontario at the time of production, appearing as his own forerunner Oliver Mowat;[26] and two different episodes in which former Dragons' Den investors Arlene Dickinson and David Chilton guest-starred.

[27] In season 17, episode 15 Margaret Atwood has a cameo as Loren Quinnell, an amateur birder, which is an interest she shared with her late husband Graeme Gibson.

[28][29] Astronaut Chris Hadfield appears as a amateur "Rocketman" in the episode Murdoch at the End of the World centering around the arrival of Halley's Comet.

In 2017, Colin Mochrie appeared on Murdoch Mysteries as a hotel detective, after joking on Twitter that he was the only Canadian actor left who had never done a guest spot on the show.

Prior to being picked up as a regular weekly series, three television movies, Except the Dying, Poor Tom Is Cold and Under the Dragon's Tail, aired on Bravo Canada in 2004.

These films starred Peter Outerbridge as William Murdoch, Matthew MacFadzean as George Crabtree, Keeley Hawes as Julia Ogden, and Colm Meaney as Inspector Brackenreid.

[35] Canadian Prime Minister Stephen Harper filmed a cameo appearance as a constable in the fourth season on October 15, 2010, when he visited the set with his daughter.

[38] In response to the cancellation of the series Christina Jennings, executive producer and CEO of Shaftesbury Films said: We've watched the show grow with the passionate support of audiences in Canada and around the world, and look forward to bringing the storyline to a fulfilling conclusion for fans during our final season.

Shaftesbury's British partners in the production of the series, broadcaster UKTV and the international distributor ITV Studios Global Entertainment, were both interested in additional seasons.

The 2013 series Nightmare on Queen Street featured an interactive story in which the viewer was called upon to solve the case by piecing together clues from each webisode.