The building was constructed under the orders of Pope Urban IV to commemorate and provide a suitable home for the Corporal of Bolsena, the relic of miracle which is said to have occurred in 1263 in the nearby town of Bolsena, when a traveling priest who had doubts about the truth of transubstantiation found that his Host was bleeding so much that it stained the altar cloth.

Situated in a position dominating the town of Orvieto which sits perched on a volcanic plug, the cathedral's façade is a classic piece of religious construction, containing elements of design from the 14th to the 20th century, with a large rose window, golden mosaics and three huge bronze doors, while inside resides two frescoed chapels decorated by some of the best Italian painters of the period with images of Judgment Day.

The flagstone of the cathedral was laid on 13 November 1290 by Pope Nicholas IV, and construction was entrusted to chief-mason (capomastro) Fra (Friar) Bevignate di Perugia (also called Fra Bevignate da Gubbio) using a design by Arnolfo di Cambio (the architect of the cathedral of Florence).

However, when Giovanni di Uguccione succeeded Fra Bevignate, the design was transformed into Italian Gothic forms.

Construction continued slowly until, in 1309, the Sienese sculptor and architect Lorenzo Maitani (universalis caput magister) was commissioned to work on the church and solve several issues concerning the load-bearing capabilities of the building, especially of the choir.

Due to the window's unusual shape, statistical and geometric techniques were used to achieve a symmetrical design.

[2] The Sienese architect Antonio Federighi continued the decoration of the façade between 1451 and 1456, adding some Renaissance modules.

The signature element is the golden frontage, which is decorated by large bas-reliefs and statues with the symbols (Angel, Ox, Lion, Eagle) of the Evangelists created by Maitani and collaborators (between 1325 and 1330) standing on the cornice above the sculptured panels on the piers.

These were finished in 1970 by the Sicilian sculptor Emilio Greco (1913–1995) depicting mercies from the life of Christ and are surmounted by a sculpture of the Madonna and Child created by Andrea Pisano in 1347.

The cathedral's side walls, in contrast to the façade, are built with alternating layers of local white travertine and blue-grey basalt stone.

It is overlooked by a fresco in International Gothic style of the "Madonna Enthroned with Child", a Maestà painted by Gentile da Fabriano in 1425.

At the beginning of the nave stands a holy water stoup, sculpted by the Sienese architect Antonio Federighi between 1451 and 1456.

Above the entrance of the Chapel of the Corporal stands the cathedral's large organ, containing 5,585 pipes and originally designed by Ippolito Scalza and Bernardino Benvenuti in the fifteenth century before being redesigned in 1913 and 1975.

Scalza's other major contribution to the church is the large Pietà he sculpted in 1579. it took him eight years to carve the four figures in this imposing marble group.

The large stained-glass quadrifore window in the apse was made between 1328 and 1334 by Giovanni di Bonino, a glass master from Assisi.

Construction of the Gothic wooden choir stalls was begun in 1329 by Giovanni Ammannati together with a group of Sienese wood carvers.

Behind the altar are a series of damaged Gothic frescoes dedicated to the life of the Virgin Mary, occupying the three walls completely.

It was painted in the Italian Byzantine tradition by the Sienese artist Lippo Memmi, brother-in-law of Simone Martini.

As a result, people began flocking in pilgrimage to the Duomo in droves from throughout central Italy, and numerous miracles were reported.

This painting is from an anonymous late 13th-century master from Orvieto, who was probably influenced by Cimabue and Coppo di Marcovaldo.

He and his school spent two years creating a series of frescoes concerning the Apocalypse and the Last Judgment, starting with the Preaching of the Antichrist, continuing with tumultuous episodes of the End of the World, finding a counterpart in the Resurrection of the Flesh.

Legend states that the writers depicted here are Homer, Empedocles, Lucan, Horace, Ovid, Virgil, and Dante, but the identifications are disputed by modern scholars.

Several small-scale grisaille medallions depicting images from their works, including the first eleven books of Dante's Purgatorio, Orpheus, Hercules, and various scenes from Ovid and Virgil, among others.

In a niche in the lower wall is shown a Pietà that contains explicit references to two important Orvietan martyr saints, S. Pietro Parenzo (podestà of Orvieto in 1199) and S. Faustino.

The figure of the dead Christ, according to Giorgio Vasari, is the image of Signorelli's son Antonio, who died from the plague during the course of the execution of the paintings.

Tomasso outlived his father and Antonio was alive when this Lamentation was delivered in February 1502, dying a few months later in July 1502."

(Preface, p. xiii) The Papal Palace attached to the right of the cathedral was originally begun in the mid-13th century when the popes moved to Orvieto to escape conflict in Rome.

Pope Boniface VIII extended the building, but it was left unfinished following the papal move to Avignon in 1309.

The ground floor of the building also houses a museum dedicated to the Sicilian artist Emilio Greco who constructed the cathedral's bronze doors in 1970.

The museum contains a wide selection of his works, as well as preparatory papers and sculptures of other large pieces, including several which are housed at St Peter's Basilica in the Vatican.