In 1971, she shot her first film entitled Leidenschaften, which documented a trip around the world with Fritz Mikesch and Rosa von Praunheim. In 1972, she did make-up and costumes for Salome directed by Werner Schroeter. She created photo series and slide shows before making a name in directing experimental films in 1980. She also worked as a documentary filmmaker for ZDF and as a camerawoman for provocative directors such as Rosa von Praunheim, Werner Schroeter, Peter Lilienthal and Monika Treut.

From 1983-84, she taught directing at the DFFB Berlin and in 1984 co-founded the independent production company Hyäne Films with Monika Treut. Since 1991, she has been a member of the Berlin Academy of Arts, Film and Media Arts. Elfi Mikesch and the filmmaker Werner Schroeter were awarded the Bielefeld Friedrich Wilhelm Murnau Filmpreis. Elfi Mikesch currently lives and works in Berlin.