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.

In 1992, Poelvoorde, Belvaux and Bonzel wrote, produced and directed together their first long feature C'est arrivé près de chez vous (Man Bites Dog internationally) originally a low-budget school graduation project (1992) and a kind of cynical satirical "noir" movie, inspired from the famous Belgian series "Strip-Tease" which went on to become a critically acclaimed cult movie.

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.

His recurrent character as a pretentious person and a sore loser has drawn comparisons between him and the beloved French comedian Louis de Funès.

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 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, who played a crucial role in the production of French writer Alexandre Dumas' Three Musketeers.