St Jerome is kneeling, half-turned to the right and looking up. He may once have been gazing at a crucifix which is now lost; before Queen Victoria acquired the painting the fine linen-like canvas was cut, probably on all sides, and laid on panel. He is dressed in a dark-green sleeveless coat, tied at the waist. In his right hand is a stone which is bloodstained from where it has been used to beat his breast. He is making an imploring gesture with his left hand. His red cardinal's hat is on the ground behind him, and to the left is a rocky background.

The strength of the drawing and refinement of the technique match those of the finest works of Perugino's early maturity; the head is very expressive and the landscape is observed with exceptional directness. Both the picture's style and technique suggest that it should be placed between the Sistine frescoes of 1481-3 and the Della Rovere polyptych of 1491 (now Villa Albani, Rome). Perugino's high reputation rested on his link with Raphael, who was thought to have been trained by him in c.1500.