The painting has the alternative title of St. Jerome in his Study. It is oil on canvas and measures 112 × 157 cm (44 in × 62 in).

St. Jerome was a popular subject matter for artists at the time of Caravaggio. He was a Roman priest and scholar who translated most of the Bible into Latin.

This version was known as the Vulgate, and Caravaggio depicts the saint in the process of working on this holy book. He is reading a large volume which rests on a table, while one arm is outstretched across two other books on the table.

St. Jerome holds a writing quill in his right hand, while his left supports the open book. He is shown as an old man, with a long white beard and a bald head with tufts of white hair each side. Above his head is the traditional halo given to a saint.

St. Jerome is half-dressed, with a red sheet wrapped around his left shoulder, concealing his lower body. This was the traditional clothing of an anchorite, a religious recluse who has withdrawn from secular society.

Their clothing would have been drab, but the rich red shade of his garment is a reference to the fact that he spent time employed as a secretary to the Pope.

This position was held in later years by a cardinal, who wears red robes. This is also a reference to the fact that the painting was owned by Cardinal Scipione Borghese, who may also have commissioned it, although no written proof of this exists.

Little can be seen of the room that St. Jerome sits in, which is dark, but an anchorite would traditionally live alone in a small cell with very little furniture or decoration. A skull sits on top of one of the books. This artistic device, called a vanitas, refers to the transience and worthlessness of earthly life.

The painting was created in Rome, where Caravaggio had enjoyed great success as an artist. His innovative use of Chiaroscuro light and shade was known as tenebrism. Unfortunately, he was involved in a violent brawl in which a man died, and this led to Caravaggio being sentenced to death.

He fled Rome, first traveling to Naples, and then to the island of Malta. While in Malta he painted another very similar painting, also called St Jerome Writing. This hangs in the Cathedral in Valetta, Malta. Caravaggio continued to paint while in exile, and attempted to obtain a pardon from the Pope, but on returning to Naples in 1609 he was involved in another violent brawl in which his face was badly disfigured. He died the following year while trying to return to Rome.