This type of painting is very durable and there are examples from the first century AD. This method of painting was highly popular until the 16th century when oil painting became the preferred method. This medium is upon a panel painting in the case of St Jerome and is believed to have been created by Andrea Mantegna. Mantegna was a painter during the Italian Renaissance. The painting was created roughly between 1449 and 1450 and can be found in the Sao Paulo Museum of Art now.

This museum resides in Brazil and holds a large collection of European artwork which includes St Jerome in the Wilderness. Often thought to be an earlier creation by Mantegna, after he left the teachings of Francesco Squarcione, an artist from Padua. After this exit, there was a shift from religious subjects to more general topics as he began to accept commissions. It is thought that this painting in particular was commissioned by Ulisse delgi Aleotti - a humanist and poet.

There was a similar painting around the same time of St Jerome in a very similar depiction but he is seen in a different pose. This painting is held at the Kupferstichkabinett Berlin, Germany. Mantegna's painting of St Jerome blends two characters together: Jerome the Scholar and Jerome the Ascetic. These two characters are the main ways of portraying St Jerome in art.

Two hammers are seen on the side of the cave behind St Jerome and could be a reference to Christ's cruxifiction. Also around the subject of the cave is an owl that is sat just near the entrance. Owls, specifically barn owls, are related to the subject of magic, superstition and the supernatural. This is particularly important because the topic of the painting, St Jerome, and the humanist and poet Ulisse delgi Aleotti face the world with reason and enlightenment in contrast. It is stark comparison between the past and the present.