The company's history goes back to the Deutsches Opernhaus built by the then independent city of Charlottenburg—the "richest town of Prussia"—according to plans designed by Heinrich Seeling from 1911. It opened on November 7, 1912 with a performance of Beethoven's Fidelio, conducted by Ignatz Waghalter. In 1925, after the incorporation of Charlottenburg by the 1920 Greater Berlin Act, the name of the resident building was changed to Städtische Oper (Municipal Opera).

With the Nazi seizure of power in 1933, the opera was under control of the Reich Ministry of Public Enlightenment and Propaganda. Minister Joseph Goebbels had the name changed back to Deutsches Opernhaus, competing with the Berlin State Opera in Mitte controlled by his rival, the Prussian minister-president Hermann Göring. In 1935, the building was remodeled by Paul Baumgarten and the seating reduced from 2300 to 2098. Carl Ebert, the pre-World War II general manager, chose to emigrate from Germany rather than endorse the Nazi view of music, and went on to co-found the Glyndebourne opera festival in England. He was replaced by Max von Schillings, who acceded to enact works of "unalloyed German character". Several artists, like the conductor Fritz Stiedry and the singer Alexander Kipnis, followed Ebert into emigration. The opera house was destroyed by a RAF air raid on 23 November 1943. Performances continued at the Admiralspalast in Mitte until 1945. Ebert returned as general manager after the war.

After the war, in what was now West Berlin, the company, again called Städtische Oper, used the nearby Theater des Westens; its opening production was Fidelio, on 4 September 1945. Its home was finally rebuilt in 1961 but to a much-changed, sober design by Fritz Bornemann. The opening production of the newly named Deutsche Oper, on 24 September, was Mozart's Don Giovanni.

Past Generalmusikdirektoren (GMD, general music directors) have included Bruno Walter, Kurt Adler, Ferenc Fricsay, Lorin Maazel, Gerd Albrecht, Jesús López-Cobos, Christian Thielemann, Renato Palumbo and Donald Runnicles.

Since 2004, the Deutsche Oper Berlin belongs to the Berlin Opera Foundation, along with the Staatsoper Unter den Linden, the Komische Oper Berlin, the Berlin State Ballet, and the Bühnenservice Berlin (Stage and Costume Design).