It portrays Saint Jerome – known for his teachings on Christian moral life – working in his study, a room without walls and ceiling viewed through an aperture (probably within a Gothic monastery).

Animals include a partridge (Alectoris graeca) and a peacock in the foreground, both having symbolical meanings, a cat, and a lion, typically associated with Saint Jerome, in the shade on the right.

It was not until 1856 that the work was positively attributed to Antonello da Messina by the art critics Giovanni Battista Cavalcaselle and Joseph Archer Crowe, who were compiling a catalogue of early Flemish painters.

The Messina scholar Carmelo Micalizzi, analysing a print reproducing the picture and observing it specularly and with magnification, has identified, in the fine drawing of some of the floor tiles, the signature, date, and place of execution of the work: ANTN, XI 1474, MISSI.

[3] In the painting, Jerome's study is shown as a raised room with three steps, set in a large Gothic building with a colonnade on the right.

The richness of the details is also reminiscent of the Flemish manner, with the careful description of the individual objects and their specific "lustre", i.e., the way each surface refracts light.

The presence of the outer frame is a compositional expedient, present in Flemish art but also cited by Leon Battista Alberti, to objectify the space of the representation, distancing it and distinguishing it from the spectator.

The "cell" of the writing desk appears perfectly organised, with its furniture, shelves, and other minute objects, such as the majolica vases for herbs.

On the ledge on which the saint's desk sits, from the left is seen a cat and two potted plants: a boxwood, which alludes to faith in divine salvation, and a geranium, a reference to the Passion of Christ.