[1] He is best known for his portrayal of Colonel William Tavington in The Patriot (2000), Michael D. Steele in Black Hawk Down (2001), Lucius Malfoy in the Harry Potter franchise series (2002–2011), Captain Hook in Peter Pan (2003), James Wolfe in Battle of the Brave (2004), Antonio Pérez in The Escorial Conspiracy (2007), Georgy Zhukov in The Death of Stalin (2017) and John Godfrey in Operation Mincemeat (2021).

His television roles include Dr. Hunter Aloysius "Hap" Percy in the Netflix supernatural mystery drama streaming series The OA (2016–2019) and Captain Gabriel Lorca in Star Trek: Discovery (2017–2018).

[8] He has said that being Jewish played a big role in his childhood, as he attended youth club in the local synagogue of King David High School in Liverpool's Childwall district, as well as a cheder twice a week as a young adult.

[9][10][11] When he was 11, he moved with his family to London and attended the Haberdashers' Aske's Boys' School in nearby Elstree at the same time as David Baddiel, Sacha Baron Cohen, Mark Kermode, and Matt Lucas.

[3][6][12] After training as an actor, Isaacs immediately began appearing on the stage and on television; his film debut was in a minor role as a doctor in Mel Smith's The Tall Guy (1989).

[12] He also played Michael Ryan in ITV's adaptation of Martina Cole's novel Dangerous Lady, directed by Jack Woods and produced by Lavinia Warner in 1995.

[12] Initially called upon to take a fairly substantial role, Isaacs was eventually cast in a much smaller capacity as a planet-saving scientist so that he could accommodate his commitment to Divorcing Jack (1998), a comedy-thriller he was making with David Thewlis.

[14] Following that he portrayed a priest opposite Julianne Moore and Ralph Fiennes in Neil Jordan's acclaimed adaptation of Graham Greene's The End of the Affair (1999).

In 2000, Isaacs appeared in the historical epic film The Patriot, opposite Mel Gibson and Heath Ledger, playing sadistic cavalry officer Colonel William Tavington.

Nonetheless, demonstrating his range beyond historic films, Isaacs next chose to play a drag queen in the romantic comedy-drama Sweet November (2001).

[20] Isaacs appeared in Black Hawk Down (2001), Jackie Chan's The Tuxedo (2002), as George Darling and Captain Hook in P. J. Hogan's adaptation of Peter Pan (2003), and as the voice of Admiral Zhao in the first season of the animated Nickelodeon series Avatar: The Last Airbender (2005).

[23][24] On American television, Isaacs appeared in three episodes of The West Wing in 2004, prior to developing his most notable TV serial role, as Michael Caffee in Brotherhood (2006–08).

Between 2 February and 24 March 2007, Isaacs played Ben, opposite Lee Evans (Gus), in the 50th-anniversary production of Harold Pinter's The Dumb Waiter, at Trafalgar Studios, in London, his first theatre performance since appearing in The Force of Change (2000).

[3][4][5][25][26] Isaacs played Major Briggs, an American military officer, opposite Matt Damon and Greg Kinnear, in Paul Greengrass's thriller Green Zone (2010), a fictionalised drama set in Iraq after the defeat of Saddam Hussein based on the book Imperial Life in the Emerald City: Inside Baghdad's Green Zone (2006), by Rajiv Chandrasekaran, for which production began in Morocco, in January 2008.

[32] On the evening of 2 May 2009, Isaacs performed the role of Ben again, opposite his Brotherhood co-star (and Tony Award winner) Brían F. O'Byrne (as Gus), in a "rehearsed reading" of The Dumb Waiter.

[citation needed] Their reading capped off the Harold Pinter Memorial Celebration being curated by Harry Burton (who had directed him and Evans at Trafalgar Studios).

Isaacs starred as Detective Michael Britten in the NBC police procedural fantasy drama series Awake, which premiered on 1 March 2012, and ended in May 2012.

Isaacs plays an FBI agent (which was named Peter Connelly) stationed in Jerusalem who uncovers a 2,000-year-old conspiracy while investigating an archaeologist's murder.

[36] It was announced in March 2017 that Isaacs would play the role of Captain Gabriel Lorca in the new CBS All Access (or Paramount+) series Star Trek: Discovery.

[41] In September 2017, Isaacs played Field Marshal Georgy Zhukov in The Death of Stalin, a political satire and dark comedy film directed by Armando Iannucci.

[42] For his performance he earned an Evening Standard British Film Awards nomination for Best Supporting Actor losing to his co-star Simon Russell Beale.

Throughout 2018 and 2019, Isaacs also voiced various characters such as the Slenderman, Alliser Thorne, Slinky and Jack the Donkey in the stop motion sketch comedy TV series Robot Chicken.

[55][57] Ahead of the 2019 UK general election, he campaigned for former Labour member Luciana Berger in her unsuccessful bid to become the Liberal Democrats' MP for the Finchley and Golders Green constituency.

[59] He traced his experience back to being 12 years old, when a bartender gave him and his friends a bottle of Southern Comfort, after which he "woke up with a splitting headache, stinking of puke with a huge scab and the memory of having utterly shamed [himself]".