In the early- and mid-1880s, the Irish Republican Brotherhood, the forerunner of the modern IRA, waged a bombing campaign that terrorized the citizens of London for more than four years. Explosives were detonated in such places as the Tower of London, the House of Commons, Victoria station and at the London Bridge. The bombings were carried out in an attempt to secure Ireland's freedom from England. The Fenians, as they were called, hoped citizens would put pressure on the government to resolve the dispute.

Implored by the government to end the reign of terror, Sherlock Holmes and Dr. Watson take up residence in a doss house in Whitechapel, which would achieve even greater notoriety a few years later courtesy of Jack the Ripper, posing as dock workers in order to learn more about the shadowy group and ingratiate themselves with its members. When Holmes learns a new bomb-maker is on the way and the bombings will increase in frequency, he understands time is running out.

Despite proving his bona fides by bombing 10 Downing Street, Holmes is still held at arm's length by the group's leader Michael. As plans for the extensive new bombing campaign are formulated, Holmes realizes that he must act quickly in order to stop the terror. However, as clever as Holmes is, Michael is his match. The Devil's Disciples pits Holmes against an adversary who is every bit as cunning as he - but far more ruthless.