According to what was handed down by Giovanni Pietro Bellori, the painting was painted by the artist for Cardinal Scipione Borghese, a refined and avid collector, known among his contemporaries for being one of the greatest admirers of the promising Lombard painter.

The painting represents Saint Jerome, doctor of the Church, intent on studying the Holy Scriptures which according to tradition were translated by him from Greek to Latin. The saint is in fact presented for his qualities as a man of studies, portrayed as an elderly humanist bent by the complex exegesis of the sacred text.

The compositional partition into two large fields of colour, characterized by warm tones - such as the saint's complexion and the purple cloak - and cold ones - the open book on which the skull stands out and the white cloth - seems to want to emphasize a symbolic dialogue between contents of opposite nature: life and death, past and present.