In 2007, while studying at the University of Cambridge, she performed in an audio production of Lady Windermere's Fan as Lady Agatha, while in 2008 she appeared in the ensemble drama Radio Cape Cod in which she plays a summer theatre camper.
She was cast in the third season (2009) of The Tudors, playing Catherine Howard, the fifth wife of Henry VIII. She debuted in the part in the third season finale and features heavily in several episodes of the fourth (and final) season.
It was announced on 20 August 2009 that Merchant would star as Daenerys Targaryen in the HBO series Game of Thrones, based on George R. R. Martin's A Song of Ice and Fire series of fantasy novels. On 29 April 2010, it was announced that Merchant was no longer part of the series, being replaced in her role as Daenerys by Emilia Clarke. She has also starred in DCI Banks: 'Playing with Fire' as Miranda. In early 2012 Merchant played the 17-year-old Rosa Bud in the BBC adaptation of Dickens' The Mystery Of Edwin Drood, written by Gwyneth Hughes (Five Days, U Be Dead, Miss Austen Regrets and Blood Strangers).