In 1891, Irene Adler delivers a package to Dr. Hoffmanstahl, payment for a letter he was to deliver. Hoffmanstahl opens the package, triggering a hidden bomb that is prevented from detonating by the intervention of Sherlock Holmes. Holmes takes the letter while Adler and Hoffmanstahl escape. Holmes finds Hoffmanstahl assassinated moments later. Adler meets with Professor Moriarty to explain the events, but Moriarty, deeming her position compromised by her love for Holmes, poisons and kills her.
Later, Dr. Watson arrives at 221B Baker Street, where Holmes discloses that he is investigating a series of seemingly unrelated murders, terrorist attacks and business acquisitions around the globe that he has connected to Moriarty. After meeting up with his brother Mycroft at Watson’s bachelor party, Holmes meets with Gypsy fortune-teller Simza, the intended recipient of the letter he took from Adler, sent by her brother Rene. Holmes defeats an assassin sent to kill Simza, but she flees before Holmes can interrogate her. After the wedding of Watson and Mary Morstan, Holmes meets Moriarty for the first time. Voicing his respect for Holmes’ perseverance, Moriarty informs Holmes that he murdered Adler. Holmes vengefully vows to defeat him and subtly requests Watson and Mary be left alone now that Watson is no longer working with him, but Moriarty indicates he will kill them anyway.
Moriarty’s men attack Watson and Mary on a train to their honeymoon. Holmes, having followed the pair to protect them, throws Mary from the train into a river below where she is rescued by Mycroft. After defeating Moriarty’s men, Holmes and Watson travel to Paris to locate Simza. When she is found, Holmes tells Simza that she has been targeted because Rene is working for Moriarty and may have told her about his plans. Simza takes the pair to the headquarters of an anarchist group to which she and Rene had formerly belonged. They learn that the anarchists have been forced to plant bombs for Moriarty.
The trio follows Holmes’ deduction that the bomb is in the Paris Opera. However, Holmes realizes too late that he has been tricked and that the bomb is in a nearby hotel; the bomb kills a number of assembled businessmen. Holmes discovers that the bomb was a cover for the specific assassination of Alfred Meinhard, one of the attendees, by Moriarty’s henchman, Sebastian Moran. Meinhard’s death grants Moriarty ownership of Meinhard’s arms factory in Germany. Holmes, Watson, and Simza travel there, following clues in Rene’s letters.