In 1922 Lenya was seen by her future husband, German composer Kurt Weill, during an audition for his first stage score Zaubernacht but because of his position behind the piano, she did not see him. She was cast but owing to her loyalty to her voice coach she declined the role. She accepted the part of Jenny in the first performance of The Threepenny Opera (Die Dreigroschenoper) in 1928, and the part became her breakthrough role. During the last years of the Weimar Republic, she was busy in film and theatre, and especially in Brecht-Weill plays. She made several recordings of Weill’s songs. With the rise of National Socialism in Germany, left-leaning artists were not appreciated and although not Jewish, she left the country, having become estranged from Weill. (They would later divorce and remarry.) In March 1933, she moved to Paris where she sang the leading part in Brecht-Weill’s “sung ballet”, The Seven Deadly Sins. Lenya and Weill settled in New York City on 10 September 1935. During the summer of 1936, Weill, Lenya, Paul Green and Cheryl Crawford rented a house at 277 Trumbull Avenue in Nichols, Connecticut, about two miles from Pine Brook Country Club, the summer rehearsal headquarters of the Group Theatre. Here, Green and Weill wrote the screenplay and music for the controversial Broadway play Johnny Johnson, which was titled after the most frequently occurring name on the American casualty list of World War I. During this period Lenya had a love affair with playwright Paul Green. During World War II, Lenya did a number of stage performances, recordings and radio performances, including for the Voice of America. After a badly received part in her husband’s musical The Firebrand of Florence in 1945 in New York, she withdrew from the stage. After Weill’s death in 1950, she was coaxed back to the stage. She appeared on Broadway in Barefoot in Athens and married editor George Davis.

In 1956 she won a Tony Award for her role as Jenny in Marc Blitzstein’s English version of The Threepenny Opera, the only time an Off-Broadway performance has been so honored. Lenya went on to record a number of songs from her time in Berlin, as well as songs from the American stage. Her voice had deepened with age. When she was to sing the soprano part in Rise and Fall of the City of Mahagonny and The Seven Deadly Sins, the part needed transposition to substantially lower keys. Sprechstimme was used in some famous songs in the Brecht-Weill plays but now Lenya used it even more to compensate for the shortcomings of her voice. Lenya was aware of this as a problem; in other contexts, she was very careful about fully respecting her late husband’s score. She founded the Kurt Weill Foundation for Music, to administer incomes and issues regarding rights, and to spread knowledge about Weill’s work. She was present in the studio when Louis Armstrong recorded Brecht-Weill’s “Mack the Knife”. Armstrong improvised the line “Look out for Miss Lotte Lenya!” and added her name to the list of Mack’s female conquests in the song. Her role as Vivien Leigh’s earthy friend Contessa Magda Terribili-Gonzales in the screen version of Tennessee Williams’ The Roman Spring of Mrs. Stone (1961) brought Lenya an Academy Award nomination as Best Supporting Actress. In 1963, she was cast as the SPECTRE agent Rosa Klebb in the James Bond movie From Russia with Love starring Sean Connery and Robert Shaw. In 1966, Lenya originated the role of Fräulein Schneider in the original Broadway cast of the musical Cabaret. Kander and Ebb’s score was considered by some to be inspired by Weill’s music. In 1979, two years before her death, Lotte Lenya was inducted into the American Theater Hall of Fame.

Lenya and Weill did not meet properly until 1924 through a mutual acquaintance, the writer Georg Kaiser. They married in 1926, and later divorced in 1933, only to reconcile in September 1935 after emigrating to the United States. They remarried in 1937. In 1941, the couple moved to a house of their own in New City, Rockland County, New York, roughly 50 km north of New York City. Their second marriage lasted until Weill’s death in 1950. Lenya’s second husband (1951–57) was American editor George Davis. After Davis’ death in 1957, she married artist Russell Detwiler in 1962. He was 26 years her junior but she was widowed for a third time when Detwiler died at the age of 44 in 1969. Lenya died in Manhattan of cancer in 1981, aged 83. She is buried next to Weill at Mount Repose Cemetery in Haverstraw, New York.