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Smith began her stage career as a student, performing at the Oxford Playhouse in 1952, and made her professional debut on Broadway in New Faces of '56. Over the following decades Smith established herself alongside Judi Dench as one of the most significant British theatre performers, working for the National Theatre and the Royal Shakespeare Company. On Broadway, she received Tony Award nominations for Noël Coward's Private Lives (1975) and Tom Stoppard's Night and Day (1979), and won the Tony Award for Best Actress in a Play for Lettice and Lovage (1990).

She won Academy Awards for Best Actress for The Prime of Miss Jean Brodie (1969) and Best Supporting Actress for California Suite (1978). She was Oscar-nominated for Othello (1965), Travels with My Aunt (1972), A Room with a View (1985) and Gosford Park (2001). She portrayed Professor Minerva McGonagall in the Harry Potter film series (2001–2011). She also acted in Death on the Nile (1978), Hook (1991), Sister Act (1992), The Secret Garden (1993), The Best Exotic Marigold Hotel (2012), Quartet (2012) and The Lady in the Van (2015).

Smith received newfound attention and international fame for her role as Violet Crawley in the British period drama Downton Abbey (2010–2015). The role earned her three Primetime Emmy Awards; she had previously won one for the HBO film My House in Umbria (2003). Over the course of her career she was the recipient of numerous honorary awards including the British Film Institute Fellowship in 1993, the BAFTA Fellowship in 1996 and the Society of London Theatre Special Award in 2010. Smith was made a Dame by Queen Elizabeth II in 1990.