June, 1916. With a world war raging on the continent, exhausted John H. Watson, M.D. is operating on the wounded full-time when his labors are interrupted by a knock on his door, revealing Sherlock Holmes, with a black eye, a missing tooth and a cracked rib. The story he has to tell will set in motion a series of world-changing events in the most consequential case of the detective's career.

Amid rebellion in Ireland and revolution in Russia, Germany has a secret plan to win the war and Sir William Melville of the British Secret Service dispatches the two aging friends to learn what the scheme is before it can be put into effect. In pursuit of a mysterious coded telegram sent from Berlin to an unknown recipient in Mexico, Holmes and Watson must cross the Atlantic, dodge German U-boats and assassination attempts, and evade the intrigues of young J. Edgar Hoover, while enlisting the help of a beautiful, eccentric Washington socialite as they seek to foil the schemes of Holmes's nemesis, the escaped German spymaster Von Bork.

Sherlock Holmes and the Telegram from Hell plunges Holmes into a world that eerily resembles our own, where entangling alliances, treaties, and human frailty threaten to create another cataclysm.