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Gambon appeared in many productions of works by William Shakespeare such as Othello, Hamlet, Macbeth and Coriolanus. Gambon was nominated for thirteen Olivier Awards, winning three times for A Chorus of Disapproval (1985), A View from the Bridge (1987), and Man of the Moment (1990). In 1997, Gambon made his Broadway debut in David Hare's Skylight, earning a Tony Award for Best Actor in a Play nomination.

Gambon made his film debut in Othello (1965). His other notable films include The Cook, the Thief, His Wife & Her Lover (1989), The Wings of the Dove (1997), The Insider (1999), Gosford Park (2001), Amazing Grace (2006), The King's Speech (2010), Quartet (2012), and Victoria & Abdul (2017). Gambon also appeared in the Wes Anderson films The Life Aquatic with Steve Zissou (2004) and Fantastic Mr. Fox (2009). Gambon gained wider recognition through his role of Albus Dumbledore in the Harry Potter film series from 2004 to 2011, replacing Richard Harris following his death in 2002.

For his work on television, he received four BAFTA Awards for The Singing Detective (1986), Wives and Daughters (1999), Longitude (2000), and Perfect Strangers (2001). He also received two Primetime Emmy Award nominations for Path to War (2002) and Emma (2009). Gambon's other notable projects include Cranford (2007) and The Casual Vacancy (2015). In 2017, he received the Irish Film & Television Academy Lifetime Achievement Award. In 2020, he was listed at No. 27 on The Irish Times's list of Ireland's greatest film actors.