The city museum is located in the fourteenth-century church of Santa Croce. The altarpiece of the Deposition on the main altar, painted by Luca Signorelli in 1516, is the only one among the many works on wood by the Cortonese master to still be found in its original site. The same characteristic, somewhat unusual for a museum, also occurs for the paintings placed on the side altars.

The scene of the Deposition is inserted in a large illustration of the salient moments of the Passion: at the top left the three crosses on Golgotha; in the center the Deposition, attended by the group of the Marys, the Virgin already fainted and the Magdalene; on the right San Giovanni, above which the transport of the body towards the sepulcher and the lamentation of the dead Christ are represented. Being the brotherhood dedicated to 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 of Iacopo da Varagine, a very widespread text in the Middle Ages.

Also of great importance in the Umbertide Museum are other works from the nearby church of San Francesco, including a canvas by Niccolò Circignani known as Pomarancio, depicting the Madonna and Child in glory. The museum of Santa Croce also has an important archaeological section: ceramic materials from the protohistoric age to the Hellenistic and Roman period, which attest to a long-standing presence in the area, coins dating back to the IV-V century AD from a settlement on Monte Acuto and a votive cabinet that has returned Italic-type bronzes of the schematic genre with human and animal figures, datable to the 6th-5th century BC