He received his first German Film Award for Best Actor for his roles in Das Weisse Rauschen (2001), Nichts Bereuen (2001), and Vaya con Dios (2002).

[4] He was introduced to mainstream international audiences through his breakthrough performance as Fredrick Zoller, a Nazi German war hero in Quentin Tarantino's Inglourious Basterds (2009), and appearances in films like The Bourne Ultimatum (2007), The Fifth Estate (2013), and A Most Wanted Man (2014).

In the Marvel Cinematic Universe, Brühl portrays Helmut Zemo in Captain America: Civil War (2016) and the Disney+ series The Falcon and the Winter Soldier (2021).

At age 15, Brühl landed a small part in the TV film Svens Geheimnis, played the street kid Benji in the soap opera Verbotene Liebe (Forbidden Love)(1995), and continued to feature in television series in the following years.

[13] In 1999, he appeared in his film debut as Checo in Paradise Mall (Schlaraffenland) and voiced Kom in the German version of Le château des singes.

In 2001, he continued to play main roles as the schizophrenic Lukas in Hans Weingartner's critically acclaimed debut film Das Weisse Rauschen (The White Sound), as Daniel in Nichts Bereuen (No Regrets), and as Marek in Honolulu.

Brühl reached further recognition in 2004 reuniting with filmmaker Hans Weingartner and starring as the anti-capitalist activist Jan in the internationally successful film The Edukators (Die Fetten Jahre sind vorbei).

In the same year, Brühl made his English-speaking film debut in Ladies in Lavender, starring alongside English actresses Judi Dench and Maggie Smith as Andrea Marowski, and met Queen Elizabeth II who attended its premiere.

[11] In 2007, Brühl made a cameo appearance in 2 Days in Paris, a romantic comedy film directed by French actress Julie Delpy.

In 2009, Brühl starred as Dr. Georg Rosen, a notable member of the International Safety Zone Committee in Nanjing, China, in the German-Chinese-French biographical film John Rabe.

He played Amaro in Las madres de Elna, István Thurzó in Julie Delpy's third directorial film The Countess, Tobias Hardmann in Dinosaurier – Gegen uns seht ihr alt aus!

He was introduced to mainstream U.S. audiences in the role of Fredrick Zoller, a German war hero in Quentin Tarantino's Inglourious Basterds, starring Brad Pitt, which premiered at the 2009 Cannes Film Festival to widespread acclaim.

In 2011, he starred as cybernetics engineer Álex Garel employed by his former university to design robot software in Eva, a science fiction film set in the year 2041.

He portrayed English teacher Konrad Koch who introduced Britain's football to his students in late 19th century Germany in Lessons of a Dream (Der ganz große Traum).

He played the Oak Fairy in 2 Days in New York and starred as ethnology student Dirk whose thesis is on the aging population in All Together (Et si on vivait tous ensemble?)

In 2013, he co-starred in The Fifth Estate, a film based on the founding of WikiLeaks in which Brühl played co-founder Daniel Domscheit-Berg alongside Benedict Cumberbatch as Julian Assange.

[22][23] In the same year, Brühl portrayed former Formula 1 driver Niki Lauda in the Ron Howard biographical film Rush opposite Chris Hemsworth.

He came to Vienna to meet Lauda who also flew him to the Brazilian Grand Prix to feel the racing atmosphere where he watched in the pit with the Mercedes team, putting on an earpiece to listen to conversations, and spoke to Formula 1 drivers.

In 2014, he starred in A Most Wanted Man as Maximilian alongside Philip Seymour Hoffman and Rachel McAdams, in The Face of an Angel as Thomas, and in the series The Trip as a patron at Terrace Bar.

[28] He reunited with director Wolfang Becker in one of his best performances as young writer Sebastian Zöllner in Me and Kaminski[29] and played Austrian investigative journalist Hubertus Czernin in the biographical drama Woman in Gold alongside Helen Mirren and Ryan Reynolds.

In Niki Caro's World War II film The Zookeeper's Wife (2017) about a married couple who saved hundreds of Jews, Brühl played Nazi zoologist Lutz Heck, who forced Jan and Antonina Żabiński to abandon the Warsaw Zoo.

From 2018 to 2020, he played the title role as Dr. Laszlo Kreizler in The Alienist, an American period crime drama series based on the 1994 novel by Caleb Carr, alongside Luke Evans and Dakota Fanning.

In his preparation, Brühl read about famous pioneering psychologists of the time (Sigmund Freud, Josef Breuer, and Carl Jung) and went to psychotherapy in Budapest just to get an understanding of the way they worked and thought.

The roles Brühl takes on are often morally complex characters, men who are suffering with a deep-seated darkness that threatens to weigh down their inherent humanity.

Film School Rejects remarks, "Even when embodying the role of a Nazi or another nefarious villain, Brühl manages to bring out the character's humanity — no matter how little of it there actually is".

[49] Brühl has worked in both European and American film productions in several languages (English, Catalan, Spanish, German, French, Polish, and Chinese) and played at least ten different nationalities, including Polish (Ladies in Lavender), Catalan (Salvador), Spanish (7 Days in Havana), French (2 Days in Paris), Hungarian (The Countess), German (Inglourious Basterds, Entebbe, and most German productions), Austrian (Rush, Woman in Gold), English (Burnt), American (The Alienist) and Sokovian (a fictional Eastern European country in Captain America: Civil War).

[50][4] Brühl is referred to as the "golden boy of German film" and the "undisputed ruler of the European acting elite" by The Gentleman's Journal on its May/June 2017 cover.