Both of Price's grandfathers had been Methodist ministers in black churches in Mississippi, and she sang in her church choir as a girl. Only when she graduated from the College of Education and Industrial Arts (now Central State College) in Wilberforce, Ohio, in 1948 did she decide to seek a career as a singer. She studied for four years at the Juilliard School of Music in New York City, where she worked under the former concert singer Florence Page Kimball, who remained her coach in later years. Her debut took place in April 1952 in a Broadway revival of Four Saints in Three Acts by Virgil Thomson and Gertrude Stein. Her performance in that production, which subsequently traveled to Paris, prompted Ira Gershwin (Gershwin, Ira) to choose her to sing the role of Bess in his revival of Porgy and Bess, which played in New York City from 1952 to 1954 and then toured the United States and Europe. The year 1955 saw her triumphant performance of the title role in the National Broadcasting Company's television production of Tosca, and she sang leading roles in other operas on television in the next few years.

Price's operatic stage debut did not take place until September 1957, when she appeared in the American premiere of Francis Poulenc's Les Dialogues des Carmélites at the San Francisco Opera. She continued in San Francisco until 1960, appearing in such works as Aïda, Thaïs, and The Wise Maidens. By that time she was one of the most popular lyric sopranos in the country and had also made successful appearances in Vienna in 1959 and at Milan's La Scala in May 1960.

Despite this great success, her debut at the Metropolitan Opera (Metropolitan Opera Association) in New York City was deferred until January 1961, when she appeared there in the role of Leonora in Il Trovatore. After a brilliant performance she became one of the Met's leading regular sopranos. Her later roles there included Cio-Cio-San in Madama Butterfly, Donna Anna in Don Giovanni, and Liu in Turandot.

In the 1970s Price began to devote more time to recitals, but she scored another great success in her first performance of Ariadne auf Naxos in San Francisco in October 1977. She was one of the most frequently recorded opera singers, and she was the recipient of more than 20 Grammy Awards from the American Society of Recording Arts and Sciences. She was awarded the Presidential Medal of Freedom in 1964, the National Medal of the Arts in 1985, and a lifetime achievement award from the National Academy of Recorded Arts and Sciences in 1989. She gave her farewell performance of Aïda at the Metropolitan Opera in New York in 1985 but continued to give recitals, which she described as her first love. She published a book, Aida, based on Giuseppe Verdi's opera, in 1990.