His mother was a grocer and his father a driver, who died when Poelvoorde was still a minor. He attended the Jesuit Boarding School of Godinne before he left home at 17 to take classes at the Félicien Rops Technical Institute in Namur (Belgium) where he met Rémy Belvaux. He developed a passion for theater and became noted for his atypical interpretations. Not only was he was destined to become a draughtsman, he also developed professionality as a photographer. During his graphic design studies at the École de recherche graphique in Brussels, he also became friend with André Bonzel and, together with Rémy Belvaux, realized in 1988 Pas de C4 pour Daniel Daniel, his first movie, a student short film (which he co-directed and co-wrote). It was a stylized trailer for a mock-spy film.
Poelvoorde subsequently starred in two series on the French pay-channel Canal+ and several movies such as Les Randonneurs, Le Boulet and Podium, which made him famous in France and Belgium. In 2001, he starred in Le Vélo de Ghislain Lambert, a funny and touching movie about one of his passions, bicycling. In 2002, he received the Jean Gabin Prize, which recognized the most hopeful young talents. Poelvoorde became a member of the Cannes Film Festival Jury in 2004, on Quentin Tarantino's request, a big fan of Man Bites Dog, who presided over the Jury, that year.
In 2008, his performance in the movie Astérix aux Jeux olympiques won him critical acclaim by both film critics and the public at large. His recurrent character as a pretentious person and a sore loser that he masters to perfection has drawn comparisons between him and the beloved French comedian Louis de Funès. Poelvoorde does not confine himself to goofy characters, he also played tortured roles. He has starred in 2009 as Etienne Balsan in Coco avant Chanel by Anne Fontain, with Audrey Tautou; as Jean-René in 2010 with Isabelle Carré in a charming comedy by Jean-Pierre Améris Émotifs anonymes about two extremely shy persons who fall in love, and also as August Maquet in L'autre Dumas by Safy Nebbou, alongside Gérard Depardieu and Dominique Blanc, a movie about the creative ghostwriter, Maquet, whose played a crucial role in the production of French writer Alexandre Dumas' Three Musketeers. In 2011, he won the Audience Award at the Magritte Awards.