His family name was Draghi, but, having moved to Jesi from Pergola, the family was called Pergolesi, meaning “of Pergola.” Sometime after 1720 he attended the Conservatorio dei Poveri at Naples, where he earned a high reputation as a violinist. In 1732 he was appointed maestro di cappella to the prince of Stigliano at Naples and produced a Neapolitan opera buffa, Lo frate 'nnammorato, and a mass (probably his Mass in D). Both were well received. In 1733 his opera seria Il prigionier superbo was produced. But it was the comic intermezzo La serva padrona, inserted between the acts of Il prigionier superbo, that achieved success. In 1734 Pergolesi was appointed deputy maestro di cappella of Naples, and in May he went to Rome to direct the performance of his Mass in F. His subsequent operas met with only occasional success. His health began to fail, and in 1736 he left Naples for the Franciscan monastery at Pozzuoli, near Naples, where he finished his last work, the celebrated Stabat Mater. He died in extreme poverty at age 26 and was buried at the cathedral at Pozzuoli.

When Pergolesi died, his fame had scarcely spread beyond Rome and Naples, but later in the century it grew enormously. The success of La serva padrona was largely posthumous, and it reached its peak after its performance in Paris in 1752. There it led to la guerre des bouffons (“the war of the buffoons”), with musical forgers vying to produce spurious works of Pergolesi, leaving some uncertainty about the authenticity of works attributed to him. Some of the works credited to Pergolesi by Igor Stravinsky in arrangements he made for his ballet Pulcinella (1920) are among those of doubtful authenticity.

Pergolesi's serious style is best illustrated in his Stabat Mater and in his masses, which demonstrate his ability to handle large choral and instrumental forces. His gift of comic characterization is best shown in the classic La serva padrona.