This large and impressive painting was once the left door of a now-dismembered three-partite altarpiece that most likely had an enthroned Madonna and Child as its central panel. St. Jerome is depicted as a heroic figure, his posture inspired by the classic contrapposto, or weight-shift, found in ancient sculpture, accentuated by the clinging drapery that delineates the body beneath it.

Biagio was a Florentine artist strongly influenced by his contemporaries Verrocchio and Ghirlandaio. Flemish painting might also have counted among his sources (examples of which he could have seen in Florence), reflected in his crystalline color and detailed landscapes. In the early 1480s, he worked in Rome on the wall frescoes of the Sistine Chapel alongside such artists as Botticelli and Perugino.