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The depiction of the Virgin and Child, surrounded by saints in a shared pictorial space, developed in Italian Renaissance painting from around the middle of the 15th century, as a so-called "Sacra Conversazione". It provided a contrast to the rigidly hierarchical triptych or polyptych formats of earlier periods, in which each figure was assigned its own panel.

The Virgin with Child at the centre is depicted seated in front of a southern landscape, holding the Christ Child on a cushion on her lap. The scene is made particularly intimate by the depiction of a breastfeeding mother, tenderly holding the head of the infant Christ.

On the left side of the painting, St Jerome stands clad as a hermit, his right hand firmly clasping a stone, the attribute with which he, as a penitent, is prepared to beat his chest. On the other side of the Madonna is Saint Francis, wearing a grey-brown habit with tonsure and holding the book referring to the foundation of the order in his arms. He holds up his left hand, the visible stigma on his palm pointing towards the young Jesus, whom he looks to with a serious, almost worried expression: a foreshadowing of the coming Passion of Christ. Next to him, the Madonna's unfocussed gaze into the distance can be interpreted as an expression of acceptance of her son's inevitable fate. Thus, on closer inspection, what appears to be a simple composition really contains a wealth of symbolism – a "sacred dialogue", not so much between the depicted figures, as with the viewer themselves.

Girolamo da Santacroce, also known as Girolamo Galizzi, explored the subject several times and depicted the Madonna surrounded by various saints. One example is the "Madonna with Saints Rochus and Sebastian" in the Galleria Nazionali Barberini Corsini, Rome (inv. no. 1333), a painting in a slightly smaller format, which depicts the Madonna with the same wandering gaze.