According to the popular tradition, partially supported by documents, the church was built to comply with a vow made to the Virgin Mary in 1133 by the citizens of Bergamo to protect the city from the plague that was hitting northern Italy at that time.

On the 23 of June 1449, the Senate and the Grand Council of Bergamo entrusted the management of the church to the Consorzio della Misericordia Maggiore, a prestigious association founded in 1265 by Pinamonte da Brembate, in order to preserve and enrich the artistic heritage of the Basilica.

The church opens on the square (Piazza Duomo) on its own left side, as the main façade has no entrance, being once united to the Bishops' Palace.

Notable is Giovanni da Campione's porch in the left transept, which is supported by columns departing from lions in Veronese marble.

The interior has maintained the original Romanesque Greek cross plan, with a nave and two aisles divided by piers and ending with an apse, but the decoration its largely from the 17th century Baroque renovation.

Over the tapestry of the Crucifixion (executed in Antwerp on Ludwig van Schoor's cartoons, 1698) is a painting by Luca Giordano, with the Passage of the Red Sea (1691).

Mayr established the Bergamo Conservatory at the Santa Maria Maggiore in 1805, and the church operated the school until it became an independent institution in 1908.