In film, he has appeared in Carrington (1995), Hamlet (1996), Dangerous Beauty (1998), Dark City (1998), A Knight's Tale (2001), The Legend of Zorro (2005), The Illusionist (2006), Amazing Grace (2006), The Holiday (2006), The Tourist (2010), Abraham Lincoln: Vampire Hunter (2012), Judy (2019), The Father (2020), and Old (2021).

On television, he has appeared in Middlemarch (1994), Arabian Nights (2000), Charles II: The Power and the Passion (2003), John Adams (2008), Eleventh Hour (2008–2009), Zen (2011), The Pillars of the Earth (2010), Parade's End (2012), Victoria (2016–2017), The Man in the High Castle (2014–2019), The Marvelous Mrs. Maisel (2019) and The Pale Horse (2020).

[9][10] Sewell's mother subsequently lived at The Pelican, Laugharne, Carmarthenshire, formerly home to the parents of Welsh poet and writer Dylan Thomas.

[9][12] After graduating, Sewell was set up with an agent by Judi Dench, who had directed him in a play while at the Central School of Speech and Drama.

[citation needed] His breakthrough year was in 1993, in which he starred as the unpleasant Tim in Michael Winner's film Dirty Weekend.

[13] Also in 1993 Sewell starred in the BBC serial of George Eliot's Middlemarch and on stage in Tom Stoppard's play Arcadia at The Royal National Theatre (Lyttelton).

The series' cast included Ian McDiarmid, Helen McCrory, Rupert Graves and Shirley Henderson and spanned the life of the king from his last days in exile to his death.

This production marked the fourth time that Sewell had acted in a work based on a Shakespeare play since becoming a professional actor: he previously portrayed Hotspur in Henry IV, Part 1 in 1995, Fortinbras in Hamlet in 1996 and the title role in Macbeth in 1999.

He continues to work in film, television and theatre, playing the lead role of Dr. Jacob Hood in the CBS TV series Eleventh Hour.

[21] Sewell played the role of Ethics Man in Darkside, Tom Stoppard's 2013 radio drama based on Pink Floyd's album The Dark Side of the Moon.

Sewell has most recently appeared as high-ranking American-turned-Nazi official John Smith in The Man in the High Castle,[24] and as Lord Melbourne in Victoria.