She was then spotted by a casting agent and appeared in the film Nach Fünf im Urwald (After Five in the Forest Primeval), directed by her then-boyfriend, Hans Christian Schmid.

[10] Following her newfound success, she starred opposite Teemu Aromaa in Downhill City (1999), a small-scale drama directed by Finnish director Hannu Salonen,[11] and in the romantic comedy Bin ich schön?, about people having trouble with love and identity, which was released on 17 September 1999 in Germany.

Out-performing Scream at the local [box office] and the biggest German pic of the year so far, this is natural latenight/fantasy fest fare that could become a cult item on half-inch and possibly even theatrically".

In the film, she portrayed a psychiatric hospital nurse who, after a near-death experience, enters into a relationship with an anguished former soldier (Benno Fürmann, also her co-star in Anatomy) who lapses into criminality.

Potente's first English-language role was that of a flight attendant who becomes engaged to cocaine smuggler George Jung in the biographical crime film Blow, alongside Johnny Depp.

In the film, she played a European woman who grows closer to the title character, a man suffering from extreme memory loss and attempting to discover his true identity amidst a clandestine conspiracy within the Central Intelligence Agency.

[25] In 2004, she starred in the British-German horror film Creep, as a woman locked in the London Underground overnight who finds herself being stalked by a hideously deformed killer living in the sewers below.

[26] ViewLondon wrote: "The performances are good, particularly Potente, who avoids scream queen clichés by making her character surprisingly unlikeable – Kate is rude and arrogant in her early scenes and the fact that she's German is, of course, a coincidence.

"[27] In 2006, Potente appeared in the German coming-of-age drama Elementarteilchen (Atomised), based on the novel Les Particules élémentaires by Michel Houellebecq and directed by Oskar Roehler.

She next starred with Eric Bana and Kodi Smit-McPhee in the Australian drama film Romulus, My Father (2007), about the struggle of a couple to raise their son amid great adversity.

Starting in May 2007, Potente had a three-episode recurring arc in the FX drama The Shield, where she played Diro Kesakhian, "the ruthless godmother of L.A.'s Armenian mafia".

[30][31] The New Yorker, pointing out Potente, remarked that "[m]ajor figures come and go, diverting the plot without registering much of an impact",[32] and The Hollywood Reporter described her part as a "small role" and felt that the actress "seems utterly uncomfortable in every scene".

Potente starred in BBC America's first original scripted series, Copper, as Eva Heissen, a shrewd German-American businesswoman and the madam of a brothel in the Five Points district of New York City during the American Civil War.

Potente subsequently had a two-episode appearance in American Horror Story: Asylum, as a woman who claims to be Holocaust victim and diarist Anne Frank.

She returned to the big screen in the horror sequel The Conjuring 2 as real-life German-British parapsychologist Anita Gregory, who investigated the Enfield Poltergeist case in the late 20th century.