Clarke was born in London, and grew up in Berkshire. Her father is a theatre sound engineer. She has a younger brother. Clarke's interest in acting began at the age of three after seeing the musical Show Boat on which her father was working. She was educated at Rye St Antony School and at St Edward's School, Oxford. She attended Drama Centre London, and graduated in 2009.
Clarke's early work includes two plays at St. Edwards, ten plays at Drama Centre London, the 2009 Company of Angels production of Sense, and two 2009 commercials for Samaritans. One of her first film roles was for a University of London students' short film. Her first television roles were Saskia Mayer in a 2009 episode of the British soap opera Doctors and Savannah in Syfy's 2010 film Triassic Attack. Screen International magazine named her as one of the "UK Stars of Tomorrow".
In 2010, Clarke was cast as Daenerys Targaryen in the HBO medieval fantasy series Game of Thrones, based on the book series A Song of Ice and Fire by George R. R. Martin.
She was cast after fellow British actress Tamzin Merchant was replaced for undisclosed reasons. She did the funky chicken and robot dance during her audition. The show debuted in April 2011 to positive reviews and was quickly picked up by the network for a second season. She has appeared in all five broadcast seasons, and is attached to the sixth. Clarke won the 2011 EWwy Award for Best Supporting Actress in a Drama for her role as Daenerys. In 2013, Clarke was nominated for Outstanding Supporting Actress in a Drama Series at the 65th Primetime Emmy Awards. She was nominated again in the category in 2015. She was voted the most desirable woman in the world by Askmen readers in 2014.
In 2012, Clarke appeared in Spike Island, a film named after the location of The Stone Roses's seminal 1990 gig. From March to April 2013, Clarke played Holly Golightly in a Broadway production of Breakfast at Tiffany's. In 2013, she also starred in Dom Hemingway alongside Jude Law. In May 2014, it was announced that she had joined the feature film Garden of Last Days alongside James Franco, but the movie was scrapped two weeks before production was due to begin. Clarke was offered the role of Anastasia Steele in Fifty Shades of Grey but turned down the part because of the nudity required. She played Sarah Connor in 2015's Terminator Genisys, opposite Arnold Schwarzenegger, Jai Courtney, and Jason Clarke. She also stars in the movie adaption of the best selling book, Me Before You, set for release on June 3, 2016, as one of the main characters, Louisa Clark.
She will play the lead as Nurse Verena, in the up-coming movie Voice from the Stone. She was named Esquire's Sexiest Woman Alive in 2015. She is also rumoured to be attached to the films The Guns of August opposite Helena Bonham Carter and Sweet Nothing.