After finishing high school in Germany, she enrolled at the Otto Falckenberg School of Performing Arts in Munich. Potente took acting jobs outside school time and appeared in her first movie in the 1995 student film, Aufbruch. She was then spotted by a casting agent and appeared in the film Nach Fünf im Urwald (It's a Jungle Out There), directed by her then-boyfriend, Hans Christian Schmid. She received the 1995 Bavarian Film Prize for Young Talent for her work in this film. She then finished her last year of training at the Lee Strasberg Theatre Institute in Manhattan.

Potente returned to Europe and worked in many German and French films. She was cast as the lead in Lola Rennt (Run Lola Run) after meeting the director, Tom Tykwer, in a café. The part was written for her and although the film was a small-budget, art house film production, it was popular in Europe. Franka Potente also performed on the soundtrack. She made several more German-language films, including the horror film, Anatomy and the romantic thriller, The Princess and the Warrior.

Her first English-language role was that of the narrator in Storytelling in 2001. This was followed by a role in Blow, with Johnny Depp, and the female lead in The Bourne Identity, with Matt Damon, which she reprised in The Bourne Supremacy. In 2006, she starred with Eric Bana in the Australian film Romulus, My Father, for which she was nominated for an Australian Film Industry Award for Best Lead Actress. Also in 2006, she wrote and directed Der die Tollkirsche ausgräbt, a silent comedy. Starting on May 22, 2007, Potente had a three-episode recurring role in FX drama The Shield, where she played Diro Kesakhian, the ruthless Godmother of LA's Armenian Mafia.

• Wave (2010) (pre-production) .... Kate
• The Cheeseburger Manifesto (2008) (pre-production) (rumored) .... Diana Tofan
• Die Brücke (2008) (TV) .... Elfie Bauer
• Che: Part Two (2008) .... Tania
• Traque, La (2008) (TV) .... Beate Klarsfeld
• Eichmann (2007) .... Vera Less
• "The Shield" .... Diro Kesakhian (3 episodes, 2007)
       - Spanish Practices (2007) TV episode .... Diro Kesakhian
       - Recoil (2007) TV episode .... Diro Kesakhian
       - The Math of the Wrath (2007) TV episode .... Diro Kesakhian
• Romulus, My Father (2007) .... Christina
• Elementarteilchen (2006) .... Annabelle
  ... aka The Elementary Particles (International: English title) (USA: festival title)
  ... aka Atomised (UK)
  ... aka Elementary Particles (USA: festival title)
• Creep (2004/I) .... Kate
  ... aka Creep (Germany)
• The Bourne Supremacy (2004) .... Marie
  ... aka Die Bourne Verschwörung (Germany)
• The Tulse Luper Suitcases, Part 2: Vaux to the Sea (2004) .... Trixie Boudain
• Blueprint (2003) .... Iris Sellin/Siri Sellin
• I Love Your Work (2003) .... Mia Lang
• Anatomie 2 (2003) .... Paula Henning
  ... aka Anatomy 2 (International: English title)
• Try Seventeen (2002) .... Jane
  ... aka All I Want (USA: DVD title)
• The Bourne Identity (2002) .... Marie
  ... aka Die Bourne Identität (Germany)