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Sherlock depicts London "consulting detective" Sherlock Holmes (Benedict Cumberbatch) in solving various mysteries. Holmes is assisted by his flatmate and friend, Dr John Watson (Martin Freeman), who has returned from military service in Afghanistan with the Royal Army Medical Corps. Although Metropolitan Police Service Detective Inspector Greg Lestrade (Rupert Graves) and others are at first skeptical of Holmes, over time his remarkable intellect and powers of observation persuade them of his value. In part through Watson's blog documenting their adventures Holmes becomes a reluctant celebrity, with the press reporting on his cases and eccentric personal life, and both ordinary people and the British government ask for his help.

Although the series depicts a variety of crimes and perpetrators, Holmes' conflict with archnemesis Jim Moriarty (Andrew Scott) is a recurring feature. Molly Hooper (Louise Brealey), a pathologist at St. Bart's Hospital occasionally assists Holmes in his cases. Other recurring roles include Una Stubbs as Mrs Hudson, Holmes and Watson's landlady, and series co-creator Mark Gatiss as Holmes' brother and top government official Mycro