Ganz had decided to pursue an acting career by the time he entered university. He was equally drawn to stage and screen but initially enjoyed greater success in the theater. In 1960, at the age of 19, he landed his first film role, in Der Herr mit der schwarzen Melone (The Man in the Black Derby). Despite the support of lead actor Gustav Knuth, his cinematic debut was not particularly successful and it was only many years later that his career in film got off the ground. Ganz made his theatrical debut the following year and devoted himself primarily to the stage for almost two decades thereafter. In 1970, he helped found the Berliner Schaubühne ensemble and two years later performed in the Salzburg Festival premier of Thomas Bernhard’s Der Ignorant und der Wahnsinnige, under the direction of Claus Peymann. The German magazine Theater heute (Theater Today) solidified Ganz’s reputation as a stage actor by pronouncing him Schauspieler des Jahres (Actor of the Year) in 1973. Perhaps his most breathtaking role was to perform for 13 hours straight as the lead in Peter Stein’s 2000 production of Goethe's Faust (Parts I and II).

Ganz’s breakthrough in cinema came with a major part in the 1976 film Sommergäste. His performance launched a distinguished career that has included important roles in both European and American films, for which he has received several of Europe’s most prized accolades. He has worked with the directors Werner Herzog, Wim Wenders, Éric Rohmer, and Francis Ford Coppola, among others. In 1979 he starred opposite Klaus Kinski in Herzog’s Nosferatu: Phantom der Nacht (Nosferatu: Phantom of the Night). More recently, in Bernd Eichinger’s much acclaimed film Der Untergang [2004] (The Downfall), Ganz may be the second native German speaker after Albin Skoda (in Georg Wilhelm Pabst's 1955 film Der letzte Akt) to play Adolf Hitler on screen, a role that most German directors had tended to relegate to very brief scenes or bit parts, often shot from behind.

Alcide Nikopol, the protagonist of the "Nikopol trilogy" of graphic novels by Enki Bilal, is clearly modelled after the likeness of a young Bruno Ganz. Ganz was born in Zürich to a Swiss mechanic father and a northern Italian mother. He is separated from his wife Sabine, whom he married in 1965, and with whom he had his only son Daniel (b.1972). When not in his hometown of Zürich, he resides in Venice and Berlin.