The Virgin Mary holds the Christ Child in her arms. Saint John hands him a ribbon with the words Agnus Dei while Saint Joseph looks on. This Latin inscription meaning Lamb of God refers to the Passion of Christ, who sacrifices himself, just as lambs were sacrified by the Jews, in order to save humanity from sin.

The composition of this scene is derived from Leonardo da Vinci's Virgin of the Spindles —now lost— which shows that the latter continued to influence Raphael right through his last works.

This painting is also called the Holy Family with a Rose, in reference to the flower o the table, although that is now considered a later addition.

There is no documentation as to when this painting arrived in Spain, but Father de los Santos lists it in the chapter of the Prior of the Monastery of El Escorial in 1667.