The work was completed by Titian during a meeting with Paul III in Ferrara, in April 1543 during a period of tension and political uncertainty leading up to the Council of Trent.

[2] The pope is depicted with unflinching realism and as an old, tired and distrustful man, but who nevertheless has an intelligent and sharp expression.

Characteristic of Titian's late style, it consists of broad brushstroke and loose definition in the form.

The artist produced a slightly different variant two years later, also preserved in Naples, which shows Paul III wearing a camauro.

The portrait of was inherited by Elisabeth Farnese, mother of Charles of Bourbon, who took it to Naples in 1734 to be exhibited in the palace of Capodimonte, where it remains today.