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, seemingly 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. Holmes subtly requests Watson and Mary be left alone now that Watson is no longer working with him, but Moriarty indicates he will kill them if Holmes interferes. Voicing his respect for Holmes' perseverance, Moriarty taunts Holmes about murdering Adler, and Holmes swears revenge.

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; its explosion 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, not wishing to repeat his mistake from the previous evening, spies on Moriarty, learning he is travelling to Germany. Holmes deduces it is to visit his newly acquired factory and so the trio follow him there.

At the factory, Moriarty captures, interrogates, and tortures Holmes while Watson fights Moran. Holmes spells out Moriarty's plot, revealing that the Professor secretly acquired shares in multiple war profiteering companies using various pseudonyms to conceal his identity and intends to instigate a world war to make himself a fortune. Meanwhile, Watson uses the cannon he had been hiding behind to destroy the watchtower in which Moran is concealed. The structure collapses into the warehouse where Moriarty is holding Holmes captive. Watson, Simza, and an injured Holmes reunite and escape aboard a moving train. Holmes deduces that Moriarty's final target will be a peace summit in Switzerland, creating an international incident.

At the summit, Holmes deduces that Rene is the assassin and that he is disguised as one of the ambassadors, having been given radical reconstructive surgery by Hoffmanstahl. Holmes and Moriarty, who is also in attendance, retreat upon a balcony to discuss their competing plans over a game of chess. Watson and Simza find Rene and stop his assassination attempt, but Rene is discreetly killed by Moran. Despite his war being averted, Moriarty remains confident in his victory, warning Holmes that the nations of Europe will inevitably go to war with one another regardless of Moriarty's manipulations. Holmes then reveals that, while being tortured by Moriarty, he replaced the professor's personal diary that contained all his plans and financing with a duplicate. The original was sent to Mary in London, who decrypted the code using a book that Holmes had noticed in Moriarty's office during their first meeting, before passing the information to Inspector Lestrade, who seizes Moriarty's assets and donates his fortune to anti-war charities. Holmes and Moriarty anticipate an impending physical altercation, and both realise that Moriarty would win due to Holmes' injured shoulder. Out of options and with the sadistic Moriarty vengefully vowing to kill Watson and Mary afterward, Holmes grabs Moriarty and lunges backwards over the balcony and into the Reichenbach Falls below. Both are presumed dead.

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