The town museum is in the 14th-century Church of Santa Croce. The altarpiece of the Deposition on the high altar, painted by Luca Signorelli in 1516, is the only one of the many works on panel by the master from Cortona that has remained at its original site. The same is true, quite unusual for a museum, of the paintings over the side altars.
The scene of the Deposition is inserted, probably at the behest of the Confraternity, in a broad portrayal of the highlights of the Passion: at the top left are the three crosses on Calvary; at the center is the Deposition, at which are present the two Marys: the Blessed Virgin, who has already fainted, and Mary Magdalene; at right is St. John, with the carrying of the body into the tomb and the mourning of the dead Christ represented above him.
Given that the confraternity is named after the Holy Cross, the three panels of the predella are dedicated to the legend of the Finding of the True Cross of Christ, in the version taken from the Golden Legend by Jacobus de Voragine, a very popular work in the Middle Ages.

Other  important works at the museum are from the nearby church of San Francesco, including a canvas by Pomarancio (Niccolò Circignani) of the Madonna and Child in Glory.

The Santa Croce museum also has an important archeological section: pottery fragments from the protohistoric age to the Hellenistic and Roman periods, which provide evidence of the long human presence in the area; coins dating from the 4th-5th centuries A.D. from a settlement on Mt. Acuto; and a votive offering including small Italic bronzes with human and animal figures, dating from the 6th-5th century B.C. These make clear reference to a pastoral society, in which ex-votos of people and animals represent requests for protection and thanks for divine intervention.