It is only a hypothesis[1] that he was formed by the Forlivese school of art, then dominated by Ansuino da Forlì; both were influenced by Andrea Mantegna.

Melozzo may have worked with Justus of Ghent and Pedro Berruguete to decorate the studiolo of the city's famous Ducal Palace.

In 1477, he finished his first major work in the new seat, a fresco now transferred to canvas and placed in the Pinacoteca Vaticana, representing Sixtus IV Appointing Platina as Librarian of the Vatican Library.

In 1478, he was one of the original members of the Academy of St Luke, founded by Sixtus IV to unite the chief painters working in the city.

In about 1472-74, Melozzo was commissioned by Pietro Riario to paint the vault of the apse in the basilica dei Santi Apostoli in Rome, his subject being the Ascension of Christ.

During this period he probably drew some cartoons for the mosaics of Jesus blessing in the Chapel of St Helena of the basilica of Santa Croce in Gerusalemme.

It has been said that he executed at Urbino some of the portraits of great men (Plato, Dante, Sixtus IV, et al) which are now divided between the Barberini Palace and the Campana collection in Paris.

Eventually Melozzo returned to Forlì, where, together with his pupil Marco Palmezzano, he decorated the Feo Chapel in the church of San Biagio, which was destroyed during World War II.