On September 6, 1894, Sherlock Holmes stares out of his window, bored that he has no case to solve that is worthy of his talents. He learns that a young Maori manservant, who works for Captain Stenwick, has mysteriously disappeared. Holmes quickly deduces not only that the boy has been kidnapped, but also that two men – one significantly larger than the other – were responsible. A few leads point to the docks by the Thames, and there, Holmes and Watson learn that similar kidnappings of foreigners have occurred. Further investigation leads them to an abandoned subterranean temple, where they discover a bloody and tortured corpse upon a sacrificial altar. They also find opium with morphine which leads Holmes to deduce that it is being used as a kind of soporific to subdue victims, so that they can be abducted and trafficked out of the country. After finding a crate labelled "Black Edelweiss Institute", Holmes recalls that the mountain flower Edelweiss (Leontopodium alpinum) is a national symbol of Switzerland.
Upon arrival it is discovered that the Black Edelweiss Institute is a Swiss mental asylum headed by a gentleman named Dr Gygax. Holmes and Watson hatch a plan to gain access and investigate. Knowing that he is about to willingly fall into the hands of criminals, Holmes sends Watson away from the asylum. This is primarily for his own safety, but also so that Holmes still has a connection with the outside world should things go awry once inside the Institute. Donning a costume and assuming a false identity, Holmes enters and is quickly incarcerated. After escaping from his cell, he finds further proof of Dr. Gygax's involvement in serious criminal activities. Not only has the doctor been performing dangerous experiments on helpless victims in the asylum, he is also part of a cult awaiting the arrival of the 'One'. Holmes unexpectedly discovers that his nemesis Moriarty is a patient, though a weakened shadow of his former self having survived the fall at Reichenbach. Using Moriarty as a distraction, Holmes extricates himself from the asylum.
Their next stop is New Orleans, as the city was mentioned in a telegram to Gygax. There, Holmes and Watson are taunted and harassed by the local sheriff who recognises them and appears to have some connection to the cult. They soon hear about a local man known as Mr. Arneson and his servant, a young lad named Davy, both of whom have been missing for days. They find Davey, who is mute due to psychological trauma. After Watson treats him, Davy writes on a chalkboard a series of numbers, which Watson copies down. Holmes and Watson then rescue Arneson, who was about to be sacrificed by a crazed cult member, and manage to retrieve an ancient book.
Back in London, Holmes and Watson learn from the book about a mythical sea god who could be awakened by the sacrificing of persons representing the different nations. They also decipher Davy's numbers, which they find are co-ordinates pointing to Ardnamurchan Lighthouse on a Scottish coastline. Once at the lighthouse, Holmes and Watson have a final confrontation with the cultists and their leader Lord Rochester, whose fortune finances the sect. Holmes manages to stop the 'summoning', but a fierce storm appears, which Rochester assumes is the coming of Cthulhu. Despite Holmes' attempt to stop him, Rochester jumps to his death into the raging sea below.