Helen Stoner needs the great man's help. She lives in a country mansion with her flamboyant and sinister guardian Grimesby Raylott, who has travelled abroad and brought home some souvenir livestock. Recently her sister Julia, about to be married and made by Raylott to sleep in a bed that was screwed to the floor, died in mysterious circumstances. Her final words referred to a "speckled band." Helen is fearful for her own safety and Holmes and Watson investigate.

Sir James Damery, acting for a very illustrious client, consults Holmes. Violet Merville is engaged to marry the Austrian Baron Gruner, who has murdered at least one wife and yet the foolish, headstrong Violet will not hear a word against him. The client is fearful for Violet's safety should the marriage go ahead. Holmes enlists the assistance of Kitty Winter, a woman whom the Baron used and threw aside, to get access to Gruner's album in which he has catalogued his conquests, to make Violet see him in his true light.

Whilst in Cornwall Holmes is approached by the local vicar to determine how Brenda Tregennis died whilst sitting in a room, playing cards with her two brothers, who were struck down with dementia as a result. The trail leads to an African adventurer and a deadly root known as the Devil's Foot.

Violet Hunter visits Sherlock Holmes for advice on whether she should accept a unique governess job with a substantial initial salary of £100 a year, on the condition that she cut her hair short, among other strange provisos. When she initially refuses, the man who made the offer, Jephro Rucastle, increases the offer to £120.

Jabez Wilson, a London pawnbroker, comes to consult Sherlock Holmes and Doctor Watson. While studying this prospective client, both Holmes and Watson notice his red hair. Wilson tells them that some weeks before, his young assistant Vincent Spaulding urged him to respond to a newspaper advertisement by "The Red-Headed League" offering highly-paid work to only red-headed male applicants.

Douglas Wilmer reads part one of this reconstructed episode. Sherlock Holmes wakes up Dr. Watson early one winter morning to rush to a murder scene at the Abbey Grange near Chislehurst, Kent. Sir Eustace Brackenstall has been killed, apparently by burglars. Inspector Stanley Hopkins believes that it was the infamous Randall gang who have committed several other burglaries in the neighbourhood.

Inspector Lestrade of Scotland Yard brings Holmes a mysterious problem about a man who shatters plaster busts of Napoleon. One was shattered in Morse Hudson's shop, and two others, sold by Hudson to a Dr. Barnicot, were smashed after the doctor's house and branch office had been burgled. Nothing else was taken. In the former case, the bust was taken outside before being broken.

A friend of Dr. Watson's wife comes to Watson's house, frantic because her husband, Isa Whitney, an opium addict, has gone missing. Watson helps her pull him out of the opium den and sends him home. Watson is surprised to find that Sherlock Holmes is there too, in disguise and trying to get information to solve a different case about a man who has disappeared. Watson stays to listen to Holmes tell the story of the case of Neville St. Clair.

A Streatham banker named Mr Alexander Holder makes a loan of £50,000 to a client from one of the "highest, noblest, most exalted names in England," implied to be a member of the British Royal Family and, thus, a son of Queen Victoria and an heir to the throne.

First half; second half soundtrack only. The monotony of thick smog-shrouded London is broken by a sudden visit from Holmes' brother Mycroft. He has come about some missing, secret submarine plans. Seven of the ten plans have been found with Arthur Cadogan West's body, but the three "most essential" papers are still missing. West was a young clerk in a government office at Royal Arsenal, Woolwich, whose body was found next to the Underground tracks near the Aldgate tube station, his head crushed.

Holmes is hired by the débutante Lady Eva Blackwell to retrieve compromising letters from a blackmailer: Milverton, who causes Holmes more revulsion than any of the 50-odd murderers in his career. Milverton is "the king of blackmailers". He demands £7,000 for the letters, which if given to third parties would cause a scandal that would end Lady Eva's marriage engagement.

Sherlock Holmes is hired by a retired art supply dealer from Lewisham, Josiah Amberley, to look into his young wife's disappearance. She has left with a neighbour, Dr Ray Ernest, taking a sizeable quantity of cash and securities. Amberley wants the two tracked down.

Sherlock Holmes sends Dr. Watson to Lausanne to investigate Lady Frances Carfax's disappearance since he himself is too busy in London. Lady Frances is a lone, unwed woman denied a rich inheritance on account of her sex. She does, however, carry valuable jewels with her. It is also her habit to write to her old governess, Miss Dobney, every other week, but for the past five weeks, there has not been a word from her.