Oper Frankfurt's orchestra came into being towards the end of the 18th century. It received its unusual name because it was also the orchestra that gave concerts for the "Frankfurter Museum", an institution founded by culturally minded people in Frankfurt in 1808, when Louis Spohr was chief conductor of the, still young, orchestra.

Many famous conductors have been linked to the orchestra during the more than two hundred years of its existence. Music Directors included Willem Mengelberg, Hermann Scherchen, Clemens Krauss and, later on, Hans Rosbaud and Franz Konwitschny. In the late 19th Century guest conductors included Gustav Mahler, Richard Strauss, Arthur Nikisch and Hans Pfitzner. Johannes Brahms and Clara Schumann performed as soloists with the Frankfurter Opern- and Museumsorchesters.

The Frankfurter Museumsgesellschaft still organises the renowned series of Museum Concerts. During the first half of the 20th Century Wilhelm Furtwängler, Hans Knappertsbusch, Hermann Abendroth, Erich Kleiber, Bruno Walter, Georges Szell and many other big names conducted here. Many new works, operatic and orchestral, including "Ein Heldenleben" and "Also sprach Zarathustra", received their world premieres in Frankfurt, played by the Frankfurter Opern- and Museumsorchester. Paul Hindemith was leader of the Frankfurter Opern- and Museumsorchester for a few years.

Since the second world war Oper Frankfurt's General Music Directors have included Georg Solti, Christoph von Dohnányi, Michael Gielen and Sylvain Cambreling, all nurturing and making their own mark on musical life in Frankfurt and the Frankfurter Opern- and Museumsorchester. Paolo Carignani was General Music Director from 1999-2007. Sebastian Weigle is now General Music Director.

The Frankfurter Opern- and Museumsorchester's huge repertoire encompasses almost all important operatic and symphonic works from the baroque to experimental contemporary music. Musicians from the orchestra also perform their own series of chamber music concerts, which take place in the opera house's Holz Foyer.