The hermit-scholar Saint Jerome was particularly venerated in humanist Florence. Here, he kneels before a crucifix, his cardinal's hat at his feet. A stream, the water of life, flows from beneath the crucifix in a landscape inhabited by various symbolic creatures. The stag signifies thirst for salvation (Psalms 42). The squirrel stands for endurance or the search for divinity. The lion, whose paw Jerome healed, is followed by a lioness; they may symbolize constancy and also the dangers the saint faced—certainly the meaning of the wyvern at bottom right. The camel alludes to Jerome's only glimpse of humanity in the wilds, the occasional camel drover.

The traditional attribution to Antonio Rossellino has to be revised. The naive but felicitous plants and animals, the drill work, and the atmospheric staging find perfect counterparts in the earliest works believed to be by Benedetto: marble reliefs (1468–71) for the shrine of Saint Savinus in Faenza Cathedral, particularly a scene of his vision, the starting point for our Jerome. In both, Benedetto abandoned the linear perspective that had preoccupied his peers in favor of an airier continuum. The foreground spilling over the bottom edge derives from the reliefs on Lorenzo Ghiberti's Gates of Paradise for the Florence Baptistery (1452).