In 1961, Placido Domingo made his operatic debut in a leading role as Alfredo in La Traviata at Monterrey and later in the same year, his debut in the United States with the Dallas Civic Opera, where he played the role of Arturo in Donizetti's Lucia di Lammermoor opposite Joan Sutherland in the title role. In 1962, he returned to Texas to play the role of Edgardo in the same opera with Lily Pons at the Fort Worth Opera.
At the end of 1962, Placido Domingo signed a six month contract with the Israel National Opera in Tel Aviv but later extended the contract and stayed for two and a half years, singing 280 performances of 12 different roles. In June 1965, after finishing his contract with Israel National Opera, Domingo went for an audition at the New York City Opera and scheduled to make his New York debut as Don Jose in Bizet's Carmen but his debut came earlier when he was asked to fill in for an ailing tenor at the last minute in Puccini's Madama Butterfly.
On 17 June 1965, Domingo made his New York debut as B. F. Pinkerton at the New York City Opera. In February 1966, he sang the title role in the U.S. premiere of Ginastera's Don Rodrigo at the New York City Opera, with much acclaim. The performance also marked the opening of the City Opera's new home at Lincoln Center. His official debut at the Metropolitan Opera in New York occurred on 28 September 1968 when he substituted for Franco Corelli, in Cilea's Adriana Lecouvreur singing with Renata Tebaldi. Before Adriana Lecouvreur, he had sung in performances by the Metropolitan Opera at Lewisohn Stadium of Mascagni's Cavalleria rusticana and Leoncavallo's Pagliacci in 1966. Since then, he has opened the season at the Metropolitan Opera 21 times, surpassing the previous record of Enrico Caruso by four. He made his debut at the Vienna State Opera in 1967, at the Lyric Opera of Chicago in 1968, at both La Scala and San Francisco Opera in 1969, at the Philadelphia Lyric Opera Company in 1970, and at Covent Garden in 1971, and has now sung at practically every other important opera house and festival worldwide.
In 1971, Placido Domingo sang Mario Cavaradossi in Puccini's Tosca at the Metropolitan Opera, and continued to sing that part for many years, singing it, in fact, more than any other role. Throughout the years, Domingo has also turned his hand to conducting opera (as early as La traviata on 7 October 1973, at New York City Opera) as well as, occasionally, symphonic orchestras. In 1981 Domingo gained considerable recognition outside of the opera world when he recorded the song "Perhaps Love" as a duet with the late American country/folk music singer John Denver. In 1987, he and Denver joined Julie Andrews for an Emmy Award winning holiday television special, The Sound of Christmas, filmed in Salzburg, Austria.
The legendary artist continued performing, singing many of the same roles but adding new roles as well, among them the title roles in Wagner's Parsifal and Mozart's Idomeneo, Rossini's Il barbiere di Siviglia as Figaro, Wagner's Die Walküre as Siegmund, Lehár's The Merry Widow as Danilo and Alfano's Cyrano de Bergerac as Cyrano. From the middle 1990s to early in 2008 alone, he added 38 new roles to his repertoire, covering opera in six different languages (English, Italian, French, German, Russian and Spanish). The latest was the Italian opera by George Frideric Handel, Tamerlano. Giving him even greater international recognition outside of the world of opera, he participated in The Three Tenors concert at the opening of the 1990 World Cup in Rome with José Carreras and Luciano Pavarotti. The event was originally conceived to raise money for the José Carreras International Leukemia Foundation and was later repeated a number of times, including at the three subsequent World Cup finals (1994 in Los Angeles, 1998 in Paris, and 2002 in Yokohama).
Alone, Domingo again made an appearance at the final of the 2006 World Cup in Berlin, along with rising stars Anna Netrebko and Rolando Villazón. On 24 August 2008, Domingo performed a duet with Song Zuying, singing Ài de Huǒyàn (The Flame of Love) at the 2008 Summer Olympics closing ceremony in Beijing. In what has been called his 'final career move', Plácido Domingo announced on 25 January 2007 that in 2009 he would take on one of Verdi's most demanding baritone roles, the Doge of Genoa, Simon Boccanegra, in the opera of the same name. The debut performance was at Berlin State Opera on October 24, followed by other 29 performances during 2009/2010 at major opera houses around the world. He would, however, continue to sing tenor roles beforehand and afterwards. On 16–17 April 2008 he sang during the visit of Pope Benedict XVI at Nationals Park and at the Italian embassy in Washington D.C.
Since 1990 Plácido Domingo has received many awards and honors for his achievement in the field of music and in recognition of his many benefit concerts and contributions to various charities. On 15 March 2009, The Metropolitan Opera paid tribute to Domingo's 40th anniversary with the company with an on-stage gala dinner at the Met's 125th anniversary, commemorating his debut in Adriana Lecouvreur as Maurizio opposite Renata Tebaldi on 28 September 1968. On 29 August 2009 he sang Panis Angelicus at the funeral mass of Senator Ted Kennedy in the Basilica of Our Lady of Perpetual Help in Boston, Massachusetts.