Born in Ixelles, a municipality of Brussels, she was attracted to theatre from early adolescence. Her first screen role was in The Motorcycle Girl (1993), a short film by Stéphan Carpiaux. After that, she played a number of roles for French television
She has stated that her idol is film actress Sandrine Bonnaire.
Régnier dated Jérémie Renier. Natacha Régnier was married to French musician Yann Tiersen, but they are now divorced.
They have a daughter. Régnier has just finished the film Une journée, which is now in post-production.