Knappertsbusch began his career as a staff conductor at the Mülheim-Ruhr Theater (1910-1912) and then as opera director in his home town of Elberfeld. Equally important to his development were his forays into the temple of Wagnerism. He spent several summers as an assistant to director Siegfried Wagner and conductor Hans Richter at the Bayreuth Festival and took part in the Netherlands Wagner Festivals in 1913 and 1914. After the end of World War I Knappertsbusch worked in Dessau and Leipzig, and in 1922 he was asked to succeed Bruno Walter as music director of the Munich Opera.
Knappertsbusch's personality was easygoing; he was notably free of the restlessness and undue ambition that often attended a rising career such as his. He was content mainly to stay in Munich, with the result that he never became as well-known as many of his colleagues. In any case, Munich fully appreciated Knappertsbusch's talents, and he was named conductor for life. However, he refused several demands made by the Nazis and was fired from his lifetime post in 1936. He conducted a memorable Salome in Covent Garden in 1936 and 1937, and made some guest appearances elsewhere in Germany, but was content to maintain a low profile during the Nazi regime. He left Germany after the Munich debacle, settling in Vienna where he frequently conducted the Philharmonic and the Vienna State Opera. Knappertsbusch's career was again affected by the Nazis when Germany took over Austria over in 1938, but he was mostly able to steer clear of trouble.
Knappertsbusch gained a reputation for broad, magisteral performances of Bruckner and, more and more, seemed emerge as the representative of the traditional style of unhurried Wagner performances. He was famous for disliking rehearsals, often cutting them short; his orchestral players maintained that this was not the result of laziness, but of complete security in his interpretation and trust of the players. His performances were therefore not rigidly preconceived, but instead had a remarkable freshness and spontaneity. When the Bayreuth Festival reopened in 1951, Knappertsbusch worked closely with Wieland Wagner on orchestral matters (though the conductor was known to dislike the director's spare, revolutionary stage productions). Perhaps Knappertsbusch's most notable recording is his stereo account of Wagner's Parsifal from the Bayreuth stage.