Giaquinto followed a kind of nomadic career. He spent extensive periods in Rome, Naples, Madrid, and Turin. The artist moved to Rome in 1723 in order to work in Sebastiano Conca's studio. During this period, he would paint in churches such as San Giovanni Calibita, San Lorenzo in Damasco, and the ceiling in Saint Cross in Jerusalem, thus raising his public recognition. In 1727, he opened an independent studio along with Giuseppe Rossi as his assistant.

Giaquinto's first documented work by his making is from a commission made by King John V of Portugal for the Mafra cathedral, dated from 1730. For this commission, he painted Saint John Evangelist, Magdalene, and Christ crucified with Madonna. In 1731, Giaquinto received an important commission to paint frescos in the church of San Nicola del Lorenesi, where he painted the Saint Nicholas water gush from a cliff, and Paradise in the cupola. Giaquinto's artwork from this period shows a stylistic move towards Luca Giordano, in detriment of his old teacher Solimena.

Giaquinto went to Turin, upon House of Savoy's director, by Filippo Juvarra's invitation. There he painted an altarpiece of St. John Nepomuk and decorated the ceiling of Villa Della Regina with the Death of Adonis, Story of Aeneid, and Triumph of the House of Savoy. He also executed other frescoes in the church of Santa Teresa, depicting events in Saint Joseph's life and death, including Rest in Egypt and his Assumption.

In the following years, the painter executed several commissions, including the Assumption of the Virgin, completed in fresco for the church in Rocca di Papa. In 1740, Giaquinto would become a member of the Academy of Saint Luke, and later in Madrid, he began working for Pope VI.

Ultimately, he was appointed as director of the Academy of San Fernando, before his death in Naples 1766. Giaquinto's influences are felt in several great artists to come, especially José del Castillo, Mariano Salvador Maella, and Antonio González Velázquez.