He was born in Waziers, and studied harmony under Maurice Durufle and conducting under André Cluytens among others at the Paris Conservatoire. After graduating, he conducted in a number of small French opera houses (sometimes under the nom de plume Georges Dherain) before making his Paris debut at the Opéra-Comique in Richard Strauss' Capriccio . His debut at the Royal Opera House, Convent Garden came in 1961, with first appearances at the Metropolitan Opera, New York City, and La Scala, Milan, later in the 1960s. He worked with Maria Callas on a number of occasions, and made recordings of Carmen and Tosca with her. For a time he was music director of the Paris Opera.
Aside from opera, Prêtre is best known for performances of French music. He is especially associated with Francis Poulenc, giving the premiere of his opera Le voix humaine at the Opéra-Comique in 1959 and his Sept répons des ténèbres in 1963. In 1999 he gave a series of concerts in Paris to celebrate the centenary of Poulenc's birth.