Weigle studied at the Hochschule für Musik "Hanns Eisler" in horn, piano and conducting. In 1987 he founded the Berlin Chamber Choir, and later he led the New Berlin Chamber Orchestra. He was principal horn player in the orchestra of the Berlin State Opera for 15 years. He also was a member of the jazz orchestra "Vielharmonie" in East Berlin.
In 1993 he became chief conductor of the National Youth Symphony Orchestra in Brandenburg and in 1997, principal conductor of the Staatsoper Unter den Linden. He has performed at many opera houses, including the Semperoper, the Frankfurt Opera, the Vienna Volksoper, the Cincinnati Opera, the Vienna State Opera and the Metropolitan Opera in New York.
In 2003, he performed Die Frau ohne Schatten by Richard Strauss at the Frankfurt Opera with director Christof Nel and was named "Conductor of the Year" by the German magazine Opernwelt. He received the title again in 2005 and 2006. From 2004 to 2008 he was music director of the Gran Teatre del Liceu in Barcelona.
Since the 2008/2009 season, Weigle has been general music director of the Frankfurt Opera, succeeding Paolo Carignani. He conducted new productions of Daphne and Arabella by Richard Strauss, Korngold's Die tote Stadt, Reimann's Lear and Die Fledermaus by Johann Strauß, and he took over Mozart's Die Zauberflöte, Beethovens Fidelio, and Wagner's Tristan und Isolde and Parsifal. He performed the four parts of Wagner's Der Ring des Nibelungen, staged by Vera Nemirova, finishing with Götterdämmerung in 2012. The complete cycle is to be performed twice in 2012. Singers have included Susan Bullock as Brünnhilde, Eva-Maria Westbroek as Sieglinde, Frank van Aken as Siegmund and Terje Stensvold as Wotan. Single performances were recorded. Gavin Dixon noted in his review of Die Walküre:
As with the previous Rhinegold recording, what really makes this Walküre distinctive is the contribution of conductor Sebastian Weigle. His patience with this music is wonderful. He knows that Wagner needs no help in building up his climaxes or creating the drama that the story needs. So tempos are usually steady, and build-ups are achieved through dynamics and orchestral colour rather than accelerando. At the start, the storm is raging in the orchestra, but it is not an all-out assault, instead it is menacing, with a steady pace and moderate dynamics. Weigle gets all the drama he needs from the tone of the orchestra and the carefully graded articulations. Similarly, The Ride of the Valkyries achieves a continuous sense of ecstatic power, but without excesses of tempo or dynamics.
- "Sebastian Weigle". Bayreuth Festival. Retrieved 5 March 2012.
- "Sebastian Weigle". Frankfurt Opera. Retrieved 7 March 2012.
- "Sebastian Weigle – conductor of Katharina Wagner's production of Meistersinger at Bayreuth". Wagneropera.net. Retrieved 5 March 2012.
- Friedeon Rosén (29 January 2012). "Frankfurt: Götterdämmerung – Premiere" (in German). der-neue-merker.eu. Retrieved 7 March 2012.
- "Der Ring des Nibelungen Cycle 1". oper-frankfurt.de. Retrieved 5 March 2012.
- Peter P. Pachl (1 November 2010). "In der Walküren-Schule: / Fortsetzung von Vera Nemirovas Frankfurter „Ring"-Inszenierung" (in German). nmz.de. Retrieved 6 March 2012.
- Julia Spinola (2 November 2010). "Meister Wotan und sein Pumuckl" (in German). Frankfurter Allgemeine Zeitung. Retrieved 6 March 2012.
- José Mª Irurzun (21 November 2011). "Fabulous Siegfried and his Aunty: Frankfurt Ring Continues". seenandheard-international.com. Retrieved 8 March 2012.
- George Loomis (21 February 2012). "German Operas Bank on Visual Effects". The New York Times. Retrieved 8 March 2012.
- Gavin Dixon (2012). "Richard Wagner (1813–1883) / Die Walküre". musicweb-international.com. Retrieved 6 March 2012.
- Blech, Volker (25 July 2007). "Die Meistersinger sind lustig". Berliner Morgenpost (in German). Berlin. Retrieved 4 August 2017.