It depicts Saint Jerome during his retreat to the Syrian desert, where he lived the life of a hermit. St Jerome kneels in a rocky landscape, gazing toward a crucifix which can be discerned faintly sketched in at the extreme right of the painting. In Jerome's right hand he holds a rock with which he is traditionally shown beating his chest in penance. At his feet is the lion which became a loyal companion after he extracted a thorn from its paw. The lion, the stone and a cardinal's hat are the traditional attributes of the saint.
On the left-hand side of the panel the background is a distant landscape of a lake surrounded by precipitous mountains shrouded in mist. To the right-hand side, the only discernible feature is a faintly-sketched church, seen through the opening in the rocks. The church's presence may allude to Jerome's position in Western Christianity as one of the Doctors of the Church.
The composition of the painting is innovative for the oblique trapezoid form of the figure of the saint. The angular forms contrast with the sinuous form of the lion which transcribes an "S" across the bottom of the painting. The form of St Jerome prefigures that of the Virgin Mary in the Madonna of the Rocks. The anatomy of the saint relates to a page of anatomical drawings of the shoulder girdle.