Roden's feature film career began almost simultaneous with his theatre work in 1984 as Honza, a medical student in the 2nd part of a trilogy entitled "How the poets are losing their illusions" (Jak básníci přicházejí o iluze), a lighthearted, comic look at life through the lives of young university students. Roden's Honza also appeared in the final installation of the trilogy, "How poets are enjoying their lives" (Jak básníkům chutná život).

During the 1990s, he spent some time in London, which improved his English and gave him necessary exposure and access to the international scene. Hence, since being outside of Czechoslovakia he has become known mostly for his character actor roles which began in 2001 when Roden secured his first major role in the American psychological thriller, 15 Minutes, where he played the Criminal Emil Slovak partnered with Oleg Taktarov opposite NYPD cop Flemming played by Robert De Niro. This was followed by a similar role, as the Lawyer Carter Kounen, in the Service of a vampire clan, in the movie Blade II in 2002.

For his main character in Guard No. 47 Karel Roden received the Czech Lion award for best actor. He also received Alfréd Radok Award in 1998 for performing Bruno in Le Cocu Magnifique by Fernand Crommelynck. Other notable role was Don Juan in Grabbe's Don Juan and Faust (Divadlo v Dlouhé). He also appeared in two plays with his brother Marian. He was also a member of the prestigious Prague National Theatre.

His movie roles to date include 15 Minutes (2001), Blade II (2002), Bulletproof Monk (2003), The Bourne Supremacy (2004), as Grigori Rasputin in Hellboy (2004), Running Scared (2006), Largo Winch (2008), RocknRolla (2008), and Orphan (2009). He also played the Russian movie critic Emil Dachevsky in the film Mr. Bean's Holiday (2007). More recently, he played Noble Thurzo in Bathory (2008), co-production movie filmed by Slovak Director Juraj Jakubisko, A Lonely Place to Die (2011) and a role as the Czech mobster Karel Benes in the TV series McMafia (2019).