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Rethberg was born Lisbeth Sättler in Schwarzenberg. She studied at the conservatory in Dresden with Otto Watrin, and she made her operatic debut in that German city opposite Richard Tauber on 16 June 1915 as Arsena in the operetta Der Zigeunerbaron by Johann Strauss II.
Rethberg sang with the Dresden Opera until 1922. In that year, she made her Metropolitan Opera debut as Aida in Giuseppe Verdi's opera of that name. She moved to the USA and remained with the Metropolitan for 20 seasons, singing 30 roles on stage and in the recording studio, opposite tenor colleagues such as Beniamino Gigli, Giovanni Martinelli and Giacomo Lauri-Volpi. Her four Met opening nights ("Die Walkure", "Marriage of Figaro", "Aida") tie her with Licia Albanese as being the sopranos who had the most Met opening nights. She also was engaged by London's Royal Opera House, Covent Garden, where she sang in 1925 and in 1934-1939. The Salzburg Festival in Austria heard her too, as did audiences in Milan and elsewhere in Europe. Rethberg returned often to Dresden where, in 1928, she created the title role in Richard Strauss's Die ägyptische Helena.
During the latter half of the 1930s, Rethberg's voice lost some of its luster, owing perhaps to the frequent singing of Aida and other heavier roles. She retired from the stage in 1942.
The most notable records of her art, however, may be the live Metropolitan recordings that include her in complete operas by Mozart, Verdi and Wagner. These recordings are somewhat difficult to obtain in America because the Met forbids their sale in the United States, owing to royalty concerns. They include Mozart's Marriage of Figaro and Verdi's Il Trovatore, Simon Boccanegra and Otello. Concerning her lieder discography, she was included in the 1930's Hugo Wolf Society recording project (e.g., "Müh'voll komm' ich und beladen").