For this artistic masterpiece, Piero used oil and tempera paint done on a panel of 180 centimetres in precise dimensions. Upon being commissioned to work on this masterpiece, Piero was instructed to be precise with colour upon a solid-gold background, which might have been his reason for using tempera paint which was being widely used in the 14th century. This kind of paint was known for its rich colour achieved through an array of colour pigments.

The Polyptych of the Misericordia was also famous for its durability, considering how long the Polyptych of the Misericordia has been around. Italian Renaissance painter Piero della Francesca was commissioned to do the painting by Compagnia della Misericordia in the year 1445 to do the painting. At the time, Piero had been working on several other paintings, leading him to breach the contract he had with Compagnia della Misericordia and that required him to finish the painting within three years. For this reason, Piero completed the Polyptych of the Misericordia seventeen years later in 1962 after starting to work on it in 1960.

As its name suggests, the Polyptych of the Misericordia was done on multiple panels which were joined together on hinging folds. Piero della Francesca skilfully worked his way through all the panels in the polyptych in a certain order, completing the central panel last. This panel the main panel and distinctly appears to be the largest from the front view of the painting. In this panel lies the Madonna della Misericordia who appears to protect her followers under her mantle.

Being larger than the other human depictions, Piero seems to emphasize the protective nature of the Virgin of Mercy through a merciful gesture of the other figures kneeling under her mantle. This religious theme is so since the Compagnia della Misericordia and was a Catholic confraternity. Moreover, major religious figures such as John the Baptist, St. Sebastian, St. Andrew and St. Bernadino are at the right and left of the central panel and at the topmost panel lies the depiction of Jesus Christ's crucifixion. From the depictions of the life of Jesus Crist, the protection of the Virgin of Mercy to the believers and the presence of the Saints, it could be understood that the Polyptych of the Misericordia was inspired by the beliefs of the Roman Catholic Church.