In 1989, Godrèche starred in Jacques Doillon's La fille de 15 ans with Melvil Poupaud, which brought her fame. The following year, she turned to a full-time career in film. In 1990 she was nominated for the César Award for Most Promising Actress for her performance in Jacquot's La désenchantée.
In 1991, she was a member of the jury at the 41st Berlin International Film Festival.
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 1998 she starred with Leonardo DiCaprio and Jeremy Irons in The Man in the Iron Mask.
Godrèche had a long-term relationship with Benoît Jacquot who was 25 years her senior. She was briefly married to Philippe Michel, an Architect, in 1996. She was later married to Comedian Dany Boon from 1998 to 2002. Together they have a son, Noé, born 4 September 1999. In 2004, she began a relationship with actor and Director Maurice Barthélémy, who is the father of her daughter, Tess, born 19 April 2005. The couple split in 2014.
Godrèche was nominated for a 2002 César Award for Best Supporting Actress for her performance in the surprise European hit, L'Auberge espagnole.
In 2012, she began playing the continuing character of Claudette Von Jurgens in season 3 of Royal Pains.
Godrèche was born in the 17th arrondissement of Paris. Her father is a psychoanalyst, and her mother a child therapist. Her parents separated when she was eight years old. Her father is Jewish; his parents were Holocaust survivors from Poland and Russia who changed their surname from Goldreich. After being discovered for her first role at the age of 14, Godrèche left school and moved away from her parents to begin her acting career. By the age of 16, she settled into a relationship with Director Benoît Jacquot, 25 years her senior.
