Detective Murdoch finds that the man behind a flying machine that crashes in Toronto is none other than his old nemesis, James Pendrick. He learns that Pendrick is hoping to win a $1 million prize for the first controlled flight. A body is found in the rubble of the crash but someone is clearly out to steal his invention. Murdoch also has to deal with Ottawa-based spymaster Terence Meyers who says it's all a national security matter. Meanwhile, Julia returns from Vienna intent on practicing psychiatry. She's also hoping to have her marriage to D'Arcy annulled.

Murdoch and Inspector Brackenreid are aboard the SS Keewatin after the owner, Clarence MacFarlane, receives what he believes is a threat. The Keewatin is about to depart from Toronto on its maiden voyage destined for Rochester, N.Y. and Murdoch thinks they should stay on board, especially after he sees that Julia is one of the invited guests. Their presence proves useful after MacFarlane's daughter Amy, who is engaged to her father's chief financial officer Owen Mathers, falls overboard and is nowhere to be found. As Murdoch investigates he finds there is a real threat against the Keewatin and the true facts behind Amy's disappearance.

Murdoch is in Bristol, England, with no memory of who he is and two gunmen chasing him through the streets. With the help of a local pub Landlady he starts to piece together an assassination plot. In Toronto Detective Hamish Sloack is assigned to help find the missing Murdoch.

Season five of Murdoch Mysteries opens in unfamiliar territory, as Detective William Murdoch (Yannick Bisson) leaves Toronto to try his luck while the Klondike Gold Rush in the Yukon winds down. Suspended for interfering in an investigation, on the run for surreptitiously freeing a murderer to make amends, and nursing a broken heart after Dr. Ogden's marriage to another man, he tries to escape his past, and his passion for detective work. Back in the city, newly promoted Chief Constable Giles (Nigel Bennett) makes it clear to Inspector Thomas Brackenreid (Thomas Craig), that he'll be keeping a very close eye on police matters. Meanwhile, Murdoch's beloved former associate, Dr. Julia Ogden (Hélène Joy), is now working alongside Acting Detective George Crabtree (Jonny Harris) and Dr. Emily Grace (Georgina Reilly), a feisty young protégé. In the remote north, Murdoch is pleased to discover that his fledgling prospecting career may garner great success, a small comfort after Julia's marriage to another man. But as he tries to rebuild his life, he finds himself drawn into the case of Mrs. Elizabeth Bryant (Jill Halfpenny), an innkeeper charged with murder. The plot thickens when writer Jack London (Aaron Ashmore) lends his insights, and Murdoch soon realizes that while he had hoped to leave his shattered heart and tattered career back in Toronto, his days as a detective are not behind him.