St. Francis looks at a skull like Hamlet at Yorick, a play released around the time this work was painted and which Caravaggio almost certainly never read. He is meditating about death, considered to be the redemption from earthly life. Each detail in the scene bears the mark of humility and penance such as the hole in the habit over his shoulder, the broken trunk and the wooden cross, which is a clear allusion to the passion of Christ. The skull and the cross mediate the dialogue between San Francesco and the divine and follow a prototypical counter-reformist iconography. St. Francis received the stigmata during one of his last prayer retreats and experienced the wounds of Christ on the cross. He is rendered kneeling down, showing partially his face. This is strategically lightened between the right cheek and the wrinkles of the forehead; we can also perceive his absorbed and suffering expression.

The canvas was found in 1968 in the church of San Pietro in Carpineto Romano. In 2000, the painting was subjected to an important restoration. This took place alongside the restoration of an almost identical version housed in the church of Santa Maria della Concezione, in Via Veneto. Researchers have confirmed the authorship of the Barberini’s canvas and its historical provenance based on the multiple corrections found in the painting that are typical of a first draft. According to some scholars, the canvas dates from around 1606. This was the year in which Caravaggio fled from Rome after murdering Ranuccio Tommasoni and found shelter in the Colonna states, that were not far from those of the Aldobrandini, commissioners of the masterpiece.