Clarke's began acting in 1997 at age nine, appearing in advertisements and stage plays. In 2000, Barnfield's won the role of bully Maddie Gilks, girlfriend to Baz Wainwright (played by Thomas Hudson), in Grange Hill, where she found herself the central role in central plots during her five-year stint on the show, It was Clarke's first major acting role.

After Grange Hill, Clarke filmed Popcorn with Jodi Albert and Jack Ryder, and plays the character of Yukino. She has also appeared in the Sky1 football drama Dream Team. Other roles include Zoe Stringer in Filthy Rich, in which she played Mike Reid's daughter shortly before he died, The Bill, where she played Chloe Fox for 3 episodes in 2004 and appeared again in October 2007 as Kelly Burgess, and Casualty in which she appeared as Claudie Waters for 2 episodes on 29 and 30 December 2007. In 2008, Clarke was the face of Clean & Clear, appearing in adverts for the skincare brand. She also starred in the Road Safety commercial 'Mess'. In 2008 she became Galaxy chocolate's 'Miss Kiss' to publicize their Christmas Mistletoe Kisses chocolates. In 2009 and 2010 she appeared in the E4 sitcom The Inbetweeners, as Neil's sister Katie in the series 2 episode "A Night Out in London" and series 3's "Will's Dilemma".

Clarke made her theatrical film debut as Crystal Waters in the Screen Gem's 3D action film Resident Evil: Afterlife, alongside Milla Jovovich, Wentworth Miller and Ali Larter. It topped the box office in September 2010. Clarke also starred in the TV movie Lake Placid 3, where she plays Ellie, this was also in 2010. In 2011 she played the lead role of Kate in Johannes Roberts' Roadkill, a horror film about a group of teens taking an ill-fated RV trip around Ireland. Her performance was well received. Clarke appeared as Barb in Jeremy Leven's 2013 movie Girl on a Bicycle.

In September 2011 Clarke was female lead of Annabel in Syfy Channel's Jabberwock opposite Battlestar Galactica's Tahmoh Penniket.