The game follows an original plotline as Sherlock Holmes and his companion Dr. John H. Watson investigate a series of strange disappearances related to the Cthulhu Mythos.
As the game begins, it is revealed that Sherlock Holmes is discontented because he lacks a case worthy of his talents. However, this mood quickly changes when Holmes learns of the disappearance of a young Maori manservant named Baowpa who worked for one of Watson's patients, Captain Stenwick.
Upon further investigation, Holmes deduces that the manservant did not simply go missing but was kidnapped. His search couples the manservant's kidnapping with other kidnappings as reported by certain interrogated individuals. It becomes apparent to Holmes that so many kidnappings could only be carried out by a powerful group of individuals -- who are later discovered to be followers of Cthulhu.
Holmes and Watson's investigation takes them to Switzerland, New Orleans, and the western Scottish coast in a desperate race against time to not only solve the case, but to prevent Cthulhu from being reawakened once more.