Based on a local legend of a spectral hound that haunted Dartmoor in Devonshire, England, the story is set in the moors at Baskerville Hall and the nearby Grimpen Mire, and the action takes place mostly at night, when the terrifying hound howls for blood. After Sir Charles Baskerville is found dead with his face twisted in stark terror, Holmes is called upon to protect his heir, Sir Henry Baskerville.

The hound of the Baskervilles is a character in Kouta Hirano's supernatural manga series Hellsing (1997–2008). Spike Milligan satirised the novel in his book, The Hound of the Baskervilles According to Spike Milligan (1997), combining elements of the original novel with the Basil Rathbone serials.