Caballé made her professional debut in Madrid in the oratorio El pesebre (The Manger) by the great Catalan cellist Pau (Pablo) Casals. She then went to Italy, where she received a few minor roles at various houses. In 1956, she joined the Basel Opera; she was working her way through the smaller roles when one of the principal singers took ill and she took over the role of Mimì in Puccini's La Bohéme. Her unqualified success in that part led to promotion to starring roles, including Pamina (The Magic Flute), Puccini's Tosca, Verdi's Aïda, Marta in Eugene d'Albert's Tiefland, and the Richard Strauss roles of Arabella, Chrysothemis (Elektra), and Salome. She steadily gained a European reputation, singing in Bremen, Milan, Vienna, Barcelona, and Lisbon, taking such diverse roles as Violetta (La Traviata), Tatiana (Yevgeny Onegin), Dvorák's Armida and Rusalka, and Marie in Berg's Wozzeck. She debuted at La Scala in 1960 as a Flower Maiden in Parsifal. She sang in Mexico City in 1964 as Massenet's Manon. In April 20, 1965, on extremely short notice, she substituted for the indisposed Marilyn Horne in a concert performance in Donizetti's Lucrezia Borgia, achieving a thunderous success and "overnight" superstardom. She became one of the leading figures in the revival of interest in the bel canto operas of Bellini and Donizetti, many of which were staged especially for her. Caballé's performances as Elizabeth I (Roberto Devereux) and that monarch's rival Mary Queen of Scots (Maria Stuarda) are legendary. In 1971, she sang a memorable concert performance of Maria Stuarda in which her fellow Barcelonian José Carreras made his London debut, and after that she helped advance his career. She made her Metropolitan Opera debut in 1965 as Marguerite in Faust. Caballé's career centered around Verdi's important dramatic roles, but also embraced the Marschallin (Der Rosenkavalier), the Countess (Marriage of Figaro), and Queen Isabella (in the premiere of Leonardo Balada's Cristobál Colón in Barcelona in 1989). Caballé had unusual crossover success. In addition to singing on two tracks on an album by new age composer Vangelis, she was famous for collaborating with Freddie Mercury of the rock group Queen, who wrote Exercises in Free Love for her. She appeared on his hit album Barcelona. That album and its primary single rose high on the pop charts.
In 1964, she married Spanish tenor Bernabé Marti. They had two children, Bernabé Marti, Jr. and Montserrat Marti, who is herself a successful soprano. In 1997, Caballé co-founded an important annual vocal competition in the Principality of Andorra, the Concurs Internacional de Cant Montserrat Caballé. She conducted master classes in conjunction with that competition. Caballé gave her last performance in 2014. She died on October 6, 2018, a few weeks after being admitted to the hospital.