Will Ferrell (Sherlock Holmes), John C. Reilly (Watson), Ralph Fiennes (Professor Moriarty), Rebecca Hall (Dr. Grace Hart), Rob Brydon (Inspector Lestrade), Kelly MacDonald (Mrs. Hudson), Pam Ferris (Königin Victoria), Steve Coogan (Gustav Klinger), Hugh Laurie (Mycroft), Hector Bateman-Harden (junger Sherlock Holmes), Lauren Lapkus (Millie), Oliver Maltman (Telegrafenbeamter), Codie-Lei Eastick (junger Watson), Bella Ramsey (Flotsam), Laura Stevely (Sherlocks Mutter), Bronson Webb (Jonathan Nightingale), Sadie Newman (Jane), David Shackleton (Albert Einstein), Harry Baxendale (Seamus), Ella Bright (Bridgette), Jason Thorpe (Butler), Jordan Long (Herbert), Kenneth Hadley (Schulleiter), Noah Jupe (Doxy), Paul Bigley (Lehrer), Paul Cassidy (Charlie Chaplin), Sue Maund (Lehrer), Phil Hodges (Mr. Algernon Barkworth), Wolf Roth (Sigmund Freud), Adam Scherr (Brawn), James Eeles (Manager Mr. Petrucka), Paul T.T. Easter (John), Samantha Sharon Watson (Elizabeth - Dame der Nacht), Sara Beasley (Mrs. Frobisher), Scarlet Grace (Pickle)