Little is known of Antonello's early life, but it is clear that he was trained in Naples, then a cosmopolitan art center, where he studied the work of Provençal and Flemish artists, especially that of Jan van Eyck. His earliest known works, a "Crucifixion" (1455) and "Saint Jerome in His Study" (1460), already show Antonello's characteristic cobination of Flemish technique and realism with typically Italian modeling of forms and clarity of spatial arrangement.
In 1457 Antonello returned to Messina, where he worked until 1474. The chief works of this period, the polyptych of 1473 and the "Annunciation" (1474), are relatively conservative altarpieces commissioned by the church, but the "Salvator Mundi" (1465), intended for private devotions, is bold and simple, showing a thorough understanding of the human form and the depiction of personality. It was but a short step from the "Salvator Mundi" to such incisive characterizations of human psychology as seen in "Portrait of a Man" (1472), a work that presaged the uncanny vitality and meticulous realism of such panels as "Portrait of a Condottiere" (1475), which established his reputation in northern Italy. His portraits are noteworthy for his characteristic use of the three-quarter view, typical of the Flemish School, whereas almost all Italian painters adopted the medal profile pose.
From 1475 to 1476 Antonello was in Venice and possibly Milan. Within a short time of his arrival in Venice, his work attracted so much favorable attention that he was supported by the Venetian state, and local painters enthusiastically adopted his oil technique and compositional style. In "Saint Sebastian" (1476), his most mature work, Antonello achieved a synthesis of clearly defined space, monumental, sculpture-like form, and luminous color, which was one of the most decisive influences on the evolution of Venetian painting down to the days of Giorgione. In 1476 Antonello was again in Messina, where he completed his final masterpiece, "The Virgin Annunciate" (1476).