Moffo took her first professional bow in 1955 as Norine in Donizetti's "Don Pasquale" in Spoleto, and later that year scored highly as Cio-Cio-San in Puccini's "Madama Butterfly" in an Italian TV production directed by Mario Lanfranchi, whom she married in 1957. Strenthening her reputation in Saltzburg and Vienna, Moffo made her U.S. debut at the Lyric Opera of Chicago in 1957 as Mimi in Puccini's "La Boheme." Her first time on the Metropolitan stage came with the role of Violetta in Verdi's "La Traviata." Over the years her bel canto repertoire would include Micaela in "Carmen," Gilda in "Rigoletto" and Liu in "Turandot." Arguably, the zenith of her Met career coincided with her appearance in the title role of Donizetti's "Lucia di Lammermoor" opposite Carlo Bergonzi's Edgardo in January of 1965. In the 1960s, Moffo also began appearing occasionally in Italian films, including feisty roles in the Napoleonic war epic Austerlitz (1960) with Rossano Brazzi; the comedy La serva padrona (1962), directed by husband Lanfranchi; Menage all'italiana (1965) [Menage, Italian Style] co-starring Ugo Tognazzi; and the comedy Il divorzio (1970) [The Divorce]. She also filmed her Violette in La traviata (1967) and Lucia di Lammermoor (1971), both directed by Lanfranchi.
The multiple Grammy-nominated Moffo's singing career was finished when just in her 40s. Taking on too much too soon (she in one year took on 12 new roles), her voice burnt out quickly. Her last regular performance at the Met was received poorly as Violetta in 1976, her voice having fallen into a serious state of disrepair. She did return briefly for a one-time duet with baritone Robert Merrill in the company's centennial gala. Her marriage to Lanfranchi ended in divorce in 1972, but her second marriage to NBC broadcast executive/RCA chairman Robert Sarnoff in 1974 proved more durable and lasted until his death in 1997. Her later years were dogged by illness. Battling breast cancer for almost a decade, Moffo died of a stroke at age 73 on March 10, 2006, in New York City. She had no children of her own but was survived by three stepchildren.