When the body of an elderly drifter is found near the docks with a whiskey flask clenched in his hands, it appears at first as if another drunk has met an unkind fate. But when Ogden determines the victim had the liver of a teetotaler, Murdoch inspects the whiskey flask and discovers a secret compartment containing what appears to be part of an encrypted message. The case takes an even stranger turn when a man identifying himself as the dead man's son comes to the morgue to claim his body. Investigations soon lead to the uncovering of political conspiracies and realizations that something far bigger is afoot than first expected.
The series takes place in Toronto in the 1890s and follows Detective William Murdoch of the Toronto Constabulary, who solves many of his cases using methods of detection that were unusual at the time. These methods include fingerprinting, blood testing, surveillance, and trace evidence.
Detective Murdoch is assisted by the three other main characters: Inspector Brackenreid, Doctor Julia Ogden, and the inexperienced but eager Constable George Crabtree, who aspires to be a mystery-novel writer. Brackenreid, Murdoch's immediate superior, is a blunt and sceptical Yorkshireman with a fondness for whiskey, and prefers conventional methods of detection over Murdoch's eccentric methods, though he is typically pleased and proud when Murdoch is successful despite the odds. Crabtree is often unable to grasp the more advanced methods, but his enthusiasm and loyalty make him a good assistant. Like Crabtree, Dr. Ogden is a great supporter of Murdoch's methods. Her skill in pathology usually helps by revealing a great deal of useful evidence to aid Murdoch in solving cases.
Throughout the series Murdoch's growing infatuation with her, and his inability to express his feelings, provide a light subplot. In the fifth season, after Dr. Ogden is married to Dr. Darcy Garland (a colleague she met in Buffalo), a new doctor is introduced, Dr. Emily Grace. She and George Crabtree show some romantic interest in each other.