The building from the crypt up to the base of the dome dates from the 15th and 16th centuries and was undertaken by the Veronese architect Michele Sanmicheli, probably with the help of Antonio da Sangallo the Younger.

[1] After a fire during the night of Good Friday in 1670 destroyed the roof and part of the interior of the cathedral, the repair and completion of the construction was entrusted to Carlo Fontana, who amended Sanmicheli's plans to produce a dome more in keeping with contemporary taste which was to impact decisively on the landscape of the surrounding countryside.

The bell towers and west front were designed and added in 1840 by the architect Paul Gazola,[1] using very simple elements of decoration: the statues of Saint Flavian of Montefiascone and Saint Margaret of Antioch, the principal saints worshipped in Montefiascone, and a classical tympanum supported by Ionic columns and surmounted by the arms of Cardinal Macchi.

[2] In 1986 the Diocese of Montefiascone was amalgamated with a number of others to form the Diocese of Viterbo, Acquapendente, Bagnoregio, Montefiascone, Tuscania e San Martino al Monte Cimino,[3] and the church ceased to be an episcopal seat.

Besides a marble statue and some relics of Saint Margaret of Antioch, the cathedral contains the relics of Saint Lucia Filippini and the tomb of Cardinal Marco Antonio Barbarigo, and also a well-known wooden cross.