It was revealed in the June/July 2008 issue of CosmoGIRL! magazine that he was a backup singer in the boyband Hyrise, who were contestants in the Eurovision Song Contest 2004. Barnes began working in television in 2006. He made his film debut in the 2007 film Stardust, portraying Young Dunstan Thorn. He later starred in Suzie Halewood's Bigga Than Ben, which will be released in August 2008.

In February 2007, it was announced Barnes would play the role of Caspian in the film adaption of The Chronicles of Narnia: Prince Caspian, directed by Andrew Adamson. Adamson said "Caspian is a coming of age and, to some degree, a loss of innocence story, with Caspian starting out quite naïve, then craving revenge and finally letting go of the vengeance." While many readers interpret Caspian as a child, a passage in the novel mentions his age to be near that of Peter's, so an older actor was sought to match William Moseley Barnes had read the novel as a child, and was cast in two-and-a-half weeks after meeting with the filmmakers. He spent two months in New Zealand horse riding and stunt training to prepare for shooting. Barnes modelled his Spanish accent on Mandy Patinkin's performance as Inigo Montoya in The Princess Bride. Adamson did not expect to cast a British actor as Caspian, and said Barnes fitted well into the surrogate family of Adamson and the four actors playing the Pevensies. When cast, Barnes was set to tour with the National Theatre's production of The History Boys: producer Mark Johnson joked Barnes "probably isn't the National [Theatre]'s favorite actor right now". Barnes left England without telling the Theatre. Barnes is also set to reprise his role of Caspian (this time as King Caspian) in the third film in the Narnia series, The Chronicles of Narnia: The Voyage of the Dawn Treader. Filming is expected to begin in October 2008 with a release date of May 7, 2010.

Barnes will be working his way around the world in June to promote Prince Caspian. In 2009, he will play John Whittaker in Easy Virtue. Barnes also has signed on for the latest version of Oscar Wilde's The Picture of Dorian Gray directed by Oliver Parker and due for a 2009 release. He is currently living in London.