If only a few traces of the Etruscan-Roman period are still present, much more documented and visible is the role played by the castle of San Venanzo in the Middle Ages and the Early Middle Ages together with that of the castles of: San Vito, Poggio Aquilone, Civitella, Rotecastello, Collelungo and Ripalvella, which marked a perpetually disputed watershed between the rival dominations of Orvieto, Marsciano, Perugia and Todi. We find the first written documents concerning the castle of San Venanzo in the Diplomatic Code of the city of Orvieto since 1200. An act of 1295 reports for example that the population refused to elect the Viscount designated by Orvieto as its administrator.
Other documents testify that in 1348 the castle was abandoned following the deadly plague epidemic that plagued Europe and that it took a few years for the population to return to celebrate the sacred rites in the church of Santo Venanzio Martire and to repopulate the castle with the renovation of destroyed houses. It is therefore very probable that the building of the church outside the walls in honour of San Rocco dates back to that time. It is indeed documented that the saint, miraculously cured of the contagion and invoked with great devotion as protector against the epidemic in his incessant pilgrimage along the entire peninsula, has left traces of his passage even in the nearby Acquapendente. Finally, reliable historical sources testify that from 1394 San Venanzo was a fief of Monaldo Monaldeschi and that in 1437 the Castle, after yet another refusal to fulfill its tax duties, was totally destroyed “ob rebellionem contra SDN, contra totam patria et contra civitatem”.