He is known for his performances as Adam Carter in Spooks, Clive Reader in Silk, DI Joseph Chandler in Whitechapel, and Mr. Quinlan in the American horror series The Strain.

[1][2] His brother, Laurence Penry-Jones (born in London, 1977), is an actor turned ambulance driver who is married to actress Polly Walker.

[9] Both productions transferred to the Barbican Centre in London,[8] where his performance as Don Carlos won the 1999 Ian Charleson Award.

[10] in 2001, he was cast as Robert Caplan in J.B. Priestley's thriller "time-play" Dangerous Corner opposite Dervla Kirwan, who played Olwen Peel at the West Yorkshire Playhouse, Leeds.

[8] From July to October 2003 at the National's Cottesloe Theatre he played the leading role of Louis XIV in Nick Dear's historical drama Power.

[9] In February 2009, Penry-Jones took the lead in an ITV drama, Whitechapel,[9] a three-part thriller based on the copycat killings of Jack the Ripper.

[13] From 2014–2017, he joined the cast of Guillermo del Toro's The Strain, playing a main role as Mr.Quinlan, a vampire-human hybrid (on the side of humans), intent on killing his father...

[14] In 2020, the release of the first trailer for The Batman revealed that he had an as-yet unannounced role in the film,[15] later reported to be that of Gotham City Mayor Don Mitchell, Jr.[16] In 2022, Penry-Jones starred as Mike/Toby in ITV 1's drama Our House alongside Martin Compston and Tuppence Middleton.