Little is known about Domenico Veneziano's early life and training. He was in Perugia (central Italy) in 1438, and from there he wrote a letter to Piero de' Medici soliciting work. He settled in Florence in 1439 and, except for brief periods, worked there until his death. It is likely that he had been in Florence prior to this date, possibly as an assistant to Gentile da Fabriano. Even his early works, in fact, reflect the influence of Florentine art, and in particular of Fra Angelico, Filippo Lippi, and Lorenzo Ghiberti.

Two signed works by Domenico survive. The first, a much-damaged fresco of the Virgin and Child enthroned and two damaged heads of saints (National Gallery, London), formed part of the “Carnesecchi Tabernacle” and may have been the first work Domenico executed in Florence. Its accurate perspective and the sculptural quality of the figures suggest he was influenced by Masaccio. The second work is an altarpiece for the Church of Santa Lucia dei Magnoli, usually called the St. Lucy altarpiece, which was probably painted about 1447. The central panel, the Virgin and Child with four saints (Uffizi, Florence), is one of the outstanding paintings produced in Florence in the middle of the 15th century. It is remarkable for the soft contours of its figures, its fresh and delicate palette, its mastery of light, and its precise and subtle space construction. The five panels of the predella are now dispersed. “The Annunciation” (Fitzwilliam Museum, Cambridge, Eng.) is the most successful of Domenico's experiments in rendering outdoor light: the pale morning light fills and defines the space of the courtyard, and the cool light on the broad plane of white wall heightens the sense of moment and loneliness in the two figures.

A tondo of the “Adoration of the Magi” (Staatliche Museen Preussischer Kulturbesitz, Berlin) is of uncertain date. It combines gay colour with careful realism and has an expansive and accurately drawn landscape background.

Domenico's two profile portraits of Matteo and Michele Olivieri (National Gallery of Art, Washington, D.C., and Rockefeller Collection, New York City) are in the tradition of Pisanello.