The film is set in 1891 and revolves around Holmes (Robert Downey, Jr.) and Watson (Jude Law) stopping a conspiracy to destroy Britain. The film opens with Holmes apprehending the murderous cult leader Lord Blackwood (Mark Strong), who promises he will return from the dead and exact his revenge as he is being led to the gallows.

In May 2009, Warner Bros. released its official plot summary:

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In a dynamic new portrayal of Arthur Conan Doyle's most famous characters, Sherlock Holmes sends Holmes and his stalwart partner Watson on their latest challenge. Revealing fighting skills as lethal as his legendary intellect, Holmes will battle as never before to bring down a new nemesis and unravel a deadly plot that could destroy the country.

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The full synopsis released in July included the following:

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The action-adventure mystery Sherlock Holmes is helmed by acclaimed filmmaker Guy Ritchie, for Warner Bros. Pictures and Village Roadshow Pictures. Robert Downey, Jr. brings the legendary detective to life, and Jude Law stars as Holmes' trusted colleague, Watson, a doctor and war veteran who is a formidable ally for Sherlock Holmes. Rachel McAdams stars as Irene Adler, the only woman ever to have bested Holmes and who has maintained a tempestuous relationship with the detective. Mark Strong stars as their mysterious new adversary, Blackwood. Kelly Reilly plays Watson's love interest, Mary. With a screenplay by Michael Robert Johnson and Anthony Peckham and Simon Kinberg, screen story by Lionel Wigram and Michael Robert Johnson, the film is produced by Joel Silver, Lionel Wigram, Susan Downey, Dan Lin and Steve Clark-Hall. Michael Tadross and Bruce Berman serve as executive producers. In theaters December 25, 2009, Sherlock Holmes will be distributed worldwide by Warner Bros. Pictures, a Warner Bros. Entertainment Company, and in selected territories by Village Roadshow Pictures.