Clotilde Hesme was born in Troyes, France in 1979. She is the sister of Annelise Hesme, and Élodie Hesme, who are also actresses. After studying at the Conservatoire National Supérieur d'Art Dramatique (CNSAD), she appeared in plays and was noticed by Jérôme Bonnel who cast her in his film Le Chignon d'Olga in 2002. In 2005 she appeared in Philippe Garrel's Regular Lovers. She was nominated for the 2008 César Award for Most Promising Actress for her role in Christophe Honoré's Love Songs. She won the César Award for Most Promising Actress in 2010 for the film Angèle et Tony.