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West made his television debut in the 1998 BBC medical drama Out of Hours before appearing in the television films A Christmas Carol, 28 Days with Sandra Bullock in 2000, and Nicholas Nickleby (2001). His breakthrough came with the role of Detective Jimmy McNulty in the series The Wire. He then starred in the BBC series The Hour (2011–2012), earning a Golden Globe Award nomination. He received a BAFTA Award for his performance as the serial killer Fred West in the ITV drama Appropriate Adult (2011) and a nomination for his portrayal as Richard Burton in BBC Four's Burton & Taylor (2013). He played Jean Valjean in the 2018 BBC miniseries adaptation of Les Misérables. He has since starred in the Netflix series Stateless (2020) and the Amazon Studios The Pursuit of Love (2021). West is currently playing the role of Dr Chris Cox in the Sky One series Brassic (2019–present).

His film debut came with his portrayal of Henry, Earl of Richmond, in Ian McKellen's adaptation of Richard III (1995). He has since appeared in Chicago (2002), Mona Lisa Smile (2003), 300 (2007), Punisher: War Zone (2008), Johnny English Reborn (2011), John Carter (2012), Pride (2014), Testament of Youth (2014), Money Monster (2016), Genius (2016), The Square (2017), Tomb Raider (2018), Colette (2018) and Downton Abbey: A New Era (2022).