The museum is situated in an old palace of Sansepolcro, the seat of the municipality until the 60s. The present aspect of the building has resulted from a number of architectural changes, which began with Galeotto Malatesta, Lord of Rimini, whose family governed Sansepolcro during the 14th century.

In 1850 various works of art were collected from the surrounding areas and placed in the museum, as well as the famous polyptych painted by Piero della Frencesca, which was transferred there in 1892 from the hospice of the local confraternity.

Piero della Francesca was born around 1412 in Sansepolcro, and today four of his works are exhibited in its Museo Civico: the Polittico della Misericordia, the polyptych commissioned in 1445 by the Confraternita della Misericordia, the “confraternity of mercy”; the Resurrection, a big fresco–the critics consider it as one of the most emblematic works of the artist–which Piero della Francesca painted on the central wall of the Sala dell’Udienza, the audience room; the fresco representing San Julian, found in 1945 in the former Sant’Agostino’s church, then become Santa Chiara’s convent; the fresco representing Saint Louise of Toulouse, removed from Palazzo Pretorio

The fulcrum of the museum is the room in which Piero frescoed the Resurrection, emblem and symbol of the city. In addition to those dedicated to Piero della Francesca, there are other 15 rooms exhibiting numerous 14th-to-20th-century works of art, along with the basement halls which contain the treasure of the Cathedral and a group of archaeological objects.