Duane Henry first began acting in 2004, a year after moving to London on November 27, 2003. Henry’s first acting role was alongside Samantha Janus on The Afternoon Play, a British television anthology series. From 2004 to 2011, Henry made a variety of guest appearances on popular British television dramas, including Doctor Who, The Bill, and The Cut, earning him a nomination for the British Academy of Film and Television Arts (BAFTA) Screen National Award for Best Emerging Talent in 2010.

From 2005 to 2013, Henry played five roles on the British medical soap opera Doctors, originally set in Birmingham. He played Gareth Broadhurst, a former soldier with PTSD in a three-part special of the show released in 2013 entitled Doctors: War Zone. Henry attributes his success on Doctors to the fact that he is a native of Birmingham and is therefore automatically considered for roles on the show. Then, in 2011, Henry played a security guard in Madonna’s historical romance drama W.E.

Henry moved from London to Los Angeles in November 2013. Shortly after moving to Los Angeles, Henry spent a year perfecting his American accent in order to expand his range as an actor. He auditioned for many roles, including a role on Jennifer Lopez's Shades of Blue, where Barry Levinson of Rain Man was also present.

Duane Henry first entered the NCIS cast as MI6 agent Clayton Reeves in May 2016 for the 23rd and 24th episodes of the show’s 13th season. It was unclear whether Henry’s character would return for the following season. In July 2016, it was confirmed that Henry’s character would be featured as a regular on the show beginning in the 14th season, which aired on September 20, 2016. According to Henry, the character of Clayton Reeves did not originally have roots in Birmingham, but he incorporated his upbringing into his character’s backstory.