The artist uses a dark background to help project that image of the saint's naked upper torso and lower body covered by a large red cloth. This painting is as realistic as it is emotional. Not only does the artist accurately depict the aged human form, the piece also shows the mood of his subject-deep contemplation. This melancholic mood of painting is quite similar to that of John the Baptist painting produced at the same time.

Caravaggio loved using Saint Jerome as a subject of his paintings because the saint was a well known figure at the time. The respected church leader, who translated the bible into Latin, featured in Caravaggio's paintings at least eight times. However, only three of these paintings survive. It is speculated that he made the paintings at the request of patrons. The power of Saint Jerome’s message was similar to Caravaggio's paintings that appealed to masses at the time.

Saint Jerome Writing painting is also known as Saint Jerome in His Study or Saint Jerome. It is believed to have been painted between 1605 and 1606, and it is currently displayed at Galleria Borghese, Rome. Just like with the Saint Jerome in meditation painting, there is a skull in this painting. In the image, Saint Jerome is writing something, and his arm is rested on a table. It is suggested that this was a depiction of Jerome translating the Vulgate. A youthful John is depicted nude, reclining, his arm around the neck of a ram and a grin on his face.

This painting is slightly different from other religious paintings by the artist as there are no symbols to signify that the subject is a prophet sent to guide others in the wilderness. Additionally, the artist uses a ram, instead of a lamb. In this painting, a lamb would have been more appropriate to symbolise Christ as the lamb of God sent to cleanse the sinful world. The model also doesn't convey a sense of sin; it is believed that he was a pagan as he was also posed for a painting depicting cupid. While several of Caravaggio's paintings were destroyed or lost, the few remaining pieces show that he was a brilliant artist. He chose subjects that were relevant at the time to produces pieces that would resonate with those people. The religious themes, however, became timeless.