In 1989, he began his stage career with a national tour in John Millington Synge's The Playboy of the Western World.

He gained recognition in film in Krzysztof Kieslowski's The Double Life of Veronique (1991), followed by his role as Claude Jade's son Jules Martin in List of Merite (1992).

In 2007, De Tonquédec started starring in the successful TV series Fais pas ci, fais pas ça, which propelled him to stardom in France alongside fellow actors Valérie Bonneton, Isabelle Gélinas and Bruno Salomone.

Co-star Valérie Benguigui won the César Award for Best Supporting Actress for her role as Élisabeth Garraud-Larchet.

De Tonquédec had been nominated two years prior for the Molière Award for Best Supporting Actor for the same role he held in the eponymous play in Paris's Théâtre Édouard VII, upon which the film was based.