Godrèche's first film appearance was as Claudia Cardinale's daughter in L'Ete prochain. The daughter of a psychiatrist, at age 14 she obtained her first screen lead in Benoit Jacquot's Les Mendiants and the following year began to pursue a full-time career film and theater.
In 1994 her novel Point de côté was published in France by Broché Publishers to good reviews.
Godrèche was not well-known to American audiences until Patrice Leconte's Ridicule was released in 1996. The film introduced her to Americans in the role of Mathilde de Bellegarde. In 1997 she starred with Leonardo DiCaprio in The Man in the Iron Mask. Her fans consider her a beauty and an example of "innocent sensuality".
She was nominated for a 2002 Cesar Award for her performance in the surprise European hit, L'Auberge espagnole.