Mikkelsen was born in the Østerbro area of Copenhagen. After attending Århus Theatre School, he made his film debut in the movie Pusher. He has starred in popular Danish movies such as Flickering Lights and The Green Butchers, but is probably best known to international audiences for his roles in King Arthur and Casino Royale. In 2006, he starred in the Oscar-nominated Danish film, After the Wedding and in 2008 appeared in Ole Christian Madsen's Flame and Citron. His most recent credits include Igor Stravinsky in the Cannes 2009 closing film, Coco Chanel & Igor Stravinsky and One-Eye in Valhalla Rising.