The story begins in 1881, where Dr. John Watson runs into an old friend, Stamford. Due to a shoulder injury sustained in the Anglo-Afghan War, Watson was forced to retire and is now looking for a place to live. Stamford reveals that an acquaintance of his, Sherlock Holmes, is looking for someone to split the rent at a flat at 221B, Baker Street.
Stamford takes Watson to the local hospital's lab, where Holmes experiments with a reagent for haemoglobin detection. Watson reveals that he is willing to split the rooms at 221B and he and Holmes list all of their faults to make sure that they accept living with each other. After seeing the rooms, the two move in.
Watson is amazed by Holmes, who has profound knowledge of chemistry and sensational literature, very precise but narrow knowledge of geology and botany; yet knows little about literature, astronomy, philosophy, and politics. Holmes also has multiple guests visiting him at different intervals during the day; he reveals to Watson that he is a consulting detective, and that his guests are clients. One of these guests turns out to be a retired Marine sergeant delivering a message from Scotland Yard about a recent murder. Holmes invites Watson to accompany him as he investigates the crime scene.
Holmes observes the sidewalk and garden leading up to the house, before he and Watson meet Inspectors Gregson and Lestrade. The four observe the crime scene and the male corpse, who is identified as Enoch Drebber. There is blood found in the room but there is no wound on the body. They also learn from documents found on his person that he was in London with a friend, Joseph Stangerson. Above his body, written in blood, is the word "RACHE", which Holmes remarks is German for revenge. He goes on to deduce that the victim died from poison, and describes what he believes the murderer looks like; six feet tall, with small feet for his height, a florid complexion, square toed boots, and smoking a Trichinopoly cigar. His fingernails on his right hand are long and he came in a cab, whose horse had three old shoes and one new one. Holmes listens to a constable's story about a drunk man loitering by the scene of the crime and informs him that the “drunk” was really the murderer revisiting the scene to collect a ring that Holmes found on the body.
Holmes puts a notice in the paper about the ring, expecting that the murderer, having already returned to the scene of the crime for it, would come to retrieve it. The advertisement is answered by an old lady who claims that the ring belongs to her daughter. Holmes follows her and, upon returning, reveals to Watson that the old lady had taken a cab, he hopped onto the back of it, and upon their arrival, the lady was nowhere to be seen; she had escaped from it, leading Holmes to believe that it was the murderer's accomplice.
The next day, Gregson visits Holmes and Watson, and tells them that he has captured the “murderer”. He had gone to Madame Charpentier's Boarding House, where Drebber and Stangerson had stayed before the Drebber's murder. He learned from her that Drebber, a drunk, had attempted to kiss Madame's daughter, Alice. She, in turn, evicted the two. Drebber, however, came back later that night and attempted to grab Alice, prompting her older brother to attack him. He attempted to chase Drebber but supposedly lost him. Gregson then went to apprehend the brother.
Lestrade then arrives, revealing that Stangerson is dead. He had gone to visit Stangerson after learning at what hotel he was staying. His body was found dead near the window, stabbed through the heart. Above his body was again written “RACHE”. The only things Stangerson had with him were a novel, a pipe, and a small box containing two pills, which Lestrade has on his person. Holmes tests the pills on an old and sickly Scottish terrier, killing it. He deduces that one was poison and the other harmless.
Just at that moment, Wiggins, a young beggar and the leader of the “Baker Street Irregulars”, a group of similar homeless beggars Holmes employs to help him occasionally, arrives, stating that he has gotten him a cab. Holmes sends him down to fetch the cabby, claiming to need help with his suitcase, but handcuffs and restrains the cabby, revealing him to be Jefferson Hope, the murderer of Drebber and Stangerson.
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