He portrayed Antonin Artaud in the Rome and London premieres of Charles Marowitz's play, Artaud at Rodez. He also portrayed the headmaster in the original National Theatre and Broadway productions of Alan Bennett's hit play, The History Boys which went on to win 6 Tony Awards and an Oliver for Best New Play. Merrison was a member of Laurence Olivier's National Theatre Company in the 1970s and the Royal Shakespeare Company, at the Royal Shakespeare Theatre in Stratford-on-Avon.

He has made numerous television appearances. He appeared as Boris Savinkov the White Russian commander in the series Reilly: Ace of Spies (1983) starring Sam Neill as Reilly. He has twice appeared in supporting roles in Doctor Who, in The Tomb of the Cybermen (1967) and Paradise Towers (1987). He has also appeared in Yes, Prime Minister, Kit Curran, The Labours of Erica, Bergerac, Drop the Dead Donkey, Time Riders, Pie in the Sky, The Tomorrow People, Mortimer's Law, The Bill, Believe Nothing, Midsomer Murders, Foyle's War, Lewis and The Brief. He played Mark's father in the 2010 Peep Show Christmas special, and also played Clement Attlee in the 2012 TV movie Bert and Dickie. He has also done voice work as a guest appearance in the children's animated series Testament: The Bible in Animation and Shakespeare: The Animated Tales.

From 5 November 1989 to 5 July 1998 he played the lead role of Sherlock Holmes on radio in a series of BBC 4 dramatisations, with Michael Williams as Dr. Watson. Later, with Andrew Sachs as Watson, Merrison continued to play Holmes in the Bert Coules-scripted pastiche series The Further Adventures of Sherlock Holmes, the first series of which was broadcast in 2002, the second in 2004, the third in 2008-9 and the fourth in 2010. He is the only actor to have played Holmes in adaptations of every single Conan Doyle short story and novel about the character.

Merrison played the onscreen father of Kate Winslet in the 1994 movie Heavenly Creatures, directed by Peter Jackson, and the traditionalist headmaster in Alan Bennett's The History Boys, filmed in 2006. He was the forger in the 1981 film Escape to Victory, and also played Thaddeus Sholto in The Sign of Four (1983), Desmond Fairchild in An Awfully Big Adventure (1995), and the Lawyer in Saving Grace (2000). His other film credits included roles in Henry VIII and His Six Wives (1972), Riddles of the Sphinx (1977), Coming Out of the Ice (1982), the Clint Eastwood film Firefox (1982), The English Patient (1996), True Blue (1996), Photographing Fairies (1997), Janice Beard (1999) and Pandaemonium (2000).

Merrison has also appeared in other BBC radio series and plays, including Groosham Grange; Burn the Aeneid! by Martyn Wade; One Winter's Afternoon; Sunday at Sant' Agata (in which he played Giuseppe Verdi); the 2003 adaptation of John Wyndham's The Midwich Cuckoos, in which he played Prof. Gordon Zellaby; Mr. Standfast; the 2011 adaptation of A Tale of Two Cities (in which he played the Marquis St. Evremonde); the 2006 radio adaptation of The History Boys (in which he played "The Headmaster", a role he repeated on film); and Strangers and Brothers.