The Church of Santa Maria Maggiore stands in Piazza del Vescovado, in front of the sixteenth-century Fountain of the Lions. It was built over a Roman-era building, the so-called House of Propertius (1st century AD), and was Assisi's first cathedral, a title that Bishop Ugone transferred to San Rufino in the 11th century.

The gable facade was rebuilt in the 12th century by a master named Giovanni; it is divided into three parts by pilasters: in the center, there is a portal whose lunette is composed of a fragment of a Roman-era fountain; the upper part is adorned with a small rose window.
The interior is divided into three naves; the walls show traces of 14th and 15th-century decoration. The presbytery, where the main altar is located, is raised above the crypt. The latter, dating back to the 9th century, is the oldest part of the structure, supported by columns and spolia capitals from an earlier period, taken from other buildings in the city.

The building is also known as the Sanctuary of the Renunciation, as it is in this square that Francis is said to have stripped naked before Bishop Guido of Assisi and his father Pietro di Bernardone, renouncing worldly possessions and riches.

The importance of the Church of Santa Maria Maggiore, as a religious center and pilgrimage destination, has been renewed in recent years, given the large number of faithful who flock to pray before the body of Carlo Acutis, who rests along the right nave of the church. The young man, beatified on October 10, 2020, by Cardinal Agostino Vallini, representing Pope Francis, lies in the urn, dressed as a young man of his age, in a sweatshirt, jeans, and sneakers.

To the side of the building stands the Bishop's Palace, built in the 17th century by Bishop Crescenzi. Inside, some rooms house the Museum of Memory, which preserves documents and photographs attesting to the support provided by the clergy of Assisi and the enclosed monasteries to Jews and political refugees during the Nazi occupation of the city (1943-1944).