Helen has appeared in many plays, television programmes and films both in Wales and throughout the United Kingdom. On television, she has been seen in the cult comedy Satellite City, Wycliffe, Life Force, Holby City and Doctor Who. Griffin's film work includes Twin Town, Solomon a Gaenor and Human Traffic.
In 2003, Griffin performed a one-woman show, Caitlin, based on the life of Caitlin MacNamara, wife of Dylan Thomas; the Western Mail praised her "finely-honed and perceptive performance".
In 2005, Griffin won acclaim for her role as Karen in Little White Lies, which she also wrote. Her performance won the Best Actress prize in the 2005 BAFTA Cymru awards, defeating expected favourite Billie Piper (who had been nominated for her role as Rose Tyler in Doctor Who). Griffin herself had become associated with Doctor Who by frequently being used as a stand-in for unavailable actors during read-throughs for other episodes.This led to her casting in the episodes "Rise of the Cybermen" and "The Age of Steel", during production of which she continued to impress the production team to the degree that the script was rewritten so that her character survived for longer than originally planned. In the final episode of "Gavin & Stacey", Helen appeared as Rita the toll woman.