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Mikkelsen achieved worldwide recognition for playing the main antagonist, Le Chiffre, in the twenty-first James Bond film, Casino Royale (2006). His other film roles include Igor Stravinsky in Coco Chanel & Igor Stravinsky (2008), Johann Friedrich Struensee in A Royal Affair (2012), his Cannes Film Festival Best Actor Award-winning performance as Lucas in the Danish film The Hunt (2012), Kaecilius in Marvel's Doctor Strange (2016), Galen Erso in Lucasfilm's Rogue One (2016), his BAFTA-nominated role as Martin in Another Round (2020), Gellert Grindelwald in Fantastic Beasts: The Secrets of Dumbledore (2022), Dr. Jürgen Voller in Indiana Jones and the Dial of Destiny (2023), and Captain Ludwig Kahlen in The Promised Land (2023). Outside of film, he is known for his roles as Dr. Hannibal Lecter in the television series Hannibal (2013–2015) and Cliff Unger in Hideo Kojima's video game Death Stranding (2019).

A. O. Scott of The New York Times remarked that in the Hollywood scene, Mikkelsen has "become a reliable character actor with an intriguing mug" but stated that on the domestic front "he is something else: a star, an axiom, a face of the resurgent Danish cinema".