Freni was born into a working-class family in Modena; her mother and tenor Luciano Pavarotti's mother worked together and an aunt was the soprano Valentina Bartolomasi. She was a musically gifted child, and when 10 years old sang "Un bel dì vedremo" in a radio competition; the tenor Beniamino Gigli warned her, however, that she risked ruining her voice and advised her to give up singing until she was older. She resumed singing at the age of 17.
Freni made her operatic debut at the Teatro Municipale in her hometown on 3 March 1955, when 20 years old, as Micaëla in Bizet's Carmen. She later married her teacher, the piano player and director Leone Magiera, resuming her career in 1958 when she performed Mimì in Puccini's La bohème at the Teatro Regio in Turin, and sang in The Netherlands Opera 1959–60 season. Her international breakthrough came at Glyndebourne, where she sang as Adina in Franco Zeffirelli's staging of Donizetti's L'elisir d'amore; in the Glyndebourne 1960–62 season she sang the Mozart comic roles of Susanna in Le nozze di Figaro and Zerlina in Don Giovanni.
In 1961, Freni made her Royal Opera House debut as Nannetta in Verdi's Falstaff, and in 1963, her La Scala debut also as Nanetta; Freni went on to become one of Herbert Von Karajan's favourite singers, working with him in operas and concerts. In 1965 she made her Metropolitan Opera debut as Mimì, and later appeared there as Liù in Puccini's Turandot, Marguerite in Faust and Juliette in Roméo et Juliette. The following year she sang Mimì again for her Philadelphia Lyric Opera Company debut, with Flaviano Labò as Rodolfo.
From the early 1970s into the 1980s Freni sang heavier Verdi roles, particularly Elisabetta in John Dexter's production of Don Carlo, Desdemona in Otello (opposite Jon Vickers), Amelia in Simon Boccanegra, Elvira in the Luca Ronconi staging of Ernani, Leonora in La forza del destino, and the title role of Aida performed in Houston in 1987. She also added the Puccini heroine Manon Lescaut and Tosca to her repertoire. Although Tosca appears to be only on record, she performed 'Manon Lescaut' in the Metropolitan Opera's 1990 Season, and recorded Madama Butterfly and the three roles of Il trittico.
An article in the April 2013 Opera News discusses Freni's approach to roles considered to be more dramatic: "Freni was a judicious singer; she never tried to give more than she had vocally, and she consistently limited her exposure to roles that she knew would be too testing. She refused Karajan's offers of Leonora in Trovatore and Turandot. Elvira in Ernani was set aside after a single run at La Scala (and despite offers to sing the role elsewhere). She recorded Cio-Cio-San twice but never sang the full role in the theater. As Freni told OPERA NEWS in 1987, 'I am generous in many ways, but not when I think it will destroy my voice. Some singers think they are gods who can do everything. But I have always been honest with myself and my possibilities.'"
Freni starred in the 1975 film Madama Butterfly opposite Plácido Domingo, with von Karajan conducting and Jean-Pierre Ponnelle directing, and in 1976, played Susanna in the Ponnelle film Le nozze di Figaro, which also featured Dietrich Fischer-Dieskau, Dame Kiri Te Kanawa and Hermann Prey.
In 1978 she married Nicolai Ghiaurov, one of the leading operatic basses of the post-war period. Together they helped to establish the Centro Universale del Bel Canto in Vignola, where they began giving master classes in 2002. Following Ghiaurov's death in 2004, Freni continued their work of preserving the bel canto tradition, and currently teaches young singers from around the world.
Freni extended her repertoire and style during the 1990s with Italian Verismo, taking on the title roles of Cilea's Adriana Lecouvreur in Milan, Paris, Barcelona and New York, and Giordano's Fedora in London, Milan, New York, Torino, Barcelona and Zürich. In 1998, she performed Giordano's Madame Sans-Gêne in Catania. During this time she sang in the Russian operas of Tchaikovsky, appearing as Tatiana in Eugene Onegin, Lisa in The Queen of Spades, and Ioanna in The Maid of Orleans.
In 2000 Mirella Freni scintillated at the 1st Herbert von Karajan Memorial concert under the baton of conductor James Allen Gähres in Ulm, where she sang together with Nicolai Ghiaurov opera arias and duets by Cilea, Tchaikovsky and Verdi.
Mirella Freni ended her professional career on stage with The Maid of Orleans at the Washington National Opera on 11 April 2005, performing the teenager Ioanna at age 70.
She was awarded the Italian Cavaliere di Gran Croce and the French Légion d'honneur in March 1993. The University of Pisa awarded her an honorary degree in 2002 for her "great contribution to European culture."
In 2005, the Metropolitan Opera celebrated the 40th anniversary of her Met debut and her 50th anniversary on the stage with a special gala concert conducted by James Levine.Freni, Mirella (1990); Mio Caro Teatro – Mirella Freni memoirs
Magiera, Leone (1990); Mirella Freni Universal Music MGB ISBN 88-7592-083-4