Antonello was trained in Naples, the Italian city most influenced by Flemish painting. He later worked in Sicily and mainland Italy. In 1475 he traveled to Venice and, while this work was painted on his return to Messina, the city visible in the background, it would not be understandable without reference to Giovanni Bellini. Bellini painted versions of the Pietà that gave Antonello a compositional reference (the placement of Christ in the foreground), as well as an iconographical one (the inclusion of angels).

Antonello's painting is technically virtuoso, combining a meticulous calligraphy of northern origin —visible in the landscape and in Christ's hair— with a monumental treatment of the anatomy and a concern for volume and perspective that are clearly southern.