Little is known of his birth, though he is thought to have been born in Venice, hence his last name. He then moved to Florence in 1422-23 as a boy, to become a pupil of Gentile da Fabriano. He is said to have worked with Pisanello in Rome around 1423-1430. One can see the influence of Benozzo Gozzoli in his work.
In a letter from him to Piero de' Medici, dated from Perugia in 1438, where he likewise resided for many years, he mentions his long connection with the fortunes of the Medici family, and begs to be allowed to paint an altar-piece for the head of that house. He was a contemporary with Fra Angelico and Fra Filippo Lippi, since those two artists and himself are known to have valued the frescoes of Buonfigli at Perugia. Between 1439 and 1441 he painted his masterpiece of the Adoration of the Magi.
One masterpiece is considered to be the St. Lucy Altarpiece (1445), originally in the Santa Lucia dei Magnoli in Florence but has been moved to the Uffizi. The painting, tempera on panel, displays such an unusual palate for this period that Vasari wrote that it had been painted in oil. He is also known for a round panel of the Adoration of the Magi (1439-1441) which was probably commissioned for the palace of the wealthy Medici family and now in Berlin. He influenced Andrea Mantegna.
He worked at the decorations of the Portinari chapel in Santa Maria Novella in Florence from 1439-1445, and had as his assistants Piero della Francesca and Bicci di Lorenzo. It is certain that whilst employed there he used linseed oil as his medium, since the hospital books of that dato make many allusions to this item in his expenses. His latter days were spent in Florence, where he died May 15, 1461, .