Domingo's parents were noted performers in zarzuela, a form of Spanish light opera. The family moved to Mexico when he was eight. He studied piano and conducting at the National Conservatory of Music, but he changed his emphasis when his rich vocal ability was revealed. In 1961 he made his operatic debut in Mexico City and then went to Dallas to perform in its opera company. From 1962 to 1965 he was a resident performer at Tel Aviv's Hebrew National Opera. He made his debut at the New York City Opera in 1965, at the Metropolitan Opera House in New York City in 1968 (subsequently becoming a regular performer there), and at La Scala in Milan in 1969. Over the course of an opera career that lasted more than 45 years, Domingo sang an unprecedented number of different roles—more than 120—and he continued to learn new parts into his 60s.

A prolific and versatile performer, Domingo made numerous recordings and several film versions of operas, and he ventured into popular music as well. With Luciano Pavarotti and José Carreras, he performed around the world as one of the “Three Tenors,” exposing millions of people to the operatic repertoire. He received 11 Grammy Awards in several categories, as well as a Kennedy Center Honor (2000), the U.S. Medal of Freedom (2002), and an honorary British knighthood (2002), among many other honours.

From 1996 he was artistic director, then from 2001 general director, of the Washington (D.C.) Opera, and from 2000 he was general director of the Los Angeles Opera. Domingo also conducted major symphony and opera orchestras in the United States and Europe. His motto, he claimed, was “If I rest, I rust.” His autobiography, My First Forty Years, was published in 1983.