The Church originated as a Romanesque building. It houses a crypt with the oldest copy of the Holy Sepulchre in Jerusalem in Europe. In 1649, with the creation of the Diocese of Acquapendente, it became the new Cathedral, until this honour was removed in 1986 when the Diocese was merged with that of Viterbo.

Important ceramic works are kept here.

Glory of the Eucharist – Jacopo Beneventano Altarpiece (transept). The work of Jacopo Parissi, known as Beneventano, this fine glazed ceramic altarpiece, dated back to 1522, was made for the deconsecrated Church of San Pietro and transferred to the Cathedral in 1881. Jacopo Beneventano made several altarpieces in the area, but this is the only preserved one, albeit with 19th-century additions and damage from World War II.

Works by Mario Vinci: Statue of St. Hermes (left apse), Deposition and Pietà (crypt, left chapel), Nativity (crypt, right chapel). Mario Vinci was born in 1934 and began his career as a ceramist at the Fuschini and Rosa factory. At the age of nineteen, he worked at the Roman studio of the Bulgarian sculptor Assen Peikov, with whom he cooperated in the creation of the sculpture ‘Leonardo Da Vinci’, erected in 1960 for Fiumicino airport. In 1961, he moved to Boston, and upon returning to Acquapendente in 1968 he opened a ceramics workshop. At the end of 1977, he started an experimental activity aimed at studying new forms of expression. In 1979, he inaugurated his workshop in the artisanal area of Paglia, where he worked until 2018, the year of his death.

Panels with the History of the Cathedral (central nave). Six panels tell the story of the Cathedral. Initially made of plaster by sculptor Ercole Drei of Bologna, they were translated into terracotta bathed in copper by Faenza master Riccardo Gatti in 1966. They depict the journey of Queen Matilda of Westphalia, on her way to Rome, and the arrival of her caravan in Acquapendente, where the queen receives an instruction to build a Church here in a dream (first pillar); the soldiers on horseback leaving for the First Crusade and the consecration of the Church by Pope Eugene III in 1149 (second pillar); the consecration of the Diocese of Acquapendente to the Madonna and finally the destruction caused by an explosion during World War II (third pillar).