The church dates back to the Middle Ages. It was founded in 874 by the queen Angilberga, wife to the Emperor Lodovico il Pio, who added a monastery for Benedictine nuns, of whom she became abbess in 882. The monastery secured rights and privileges on large areas in northern Italy. 

Through the centuries numerous orders of monks and nuns alternatively guided the monastery up to 1425, when it was assigned to the order of Cassinesi. On the original medieval complex was built the church we see today, which dates back to the 16th century. It is common belief that Alessio Tramello participated in the definition of some details such as the vault, the choir, the domes, and the temples. 

Once beyond the main portal there is a large cloister with three porticoes with 21 full arches supported by granite columns. Above the arches of the cloister are still visible ancient frescoed medallions depicting emperors or abbots. Apart from this courtyard there are two more: one for the abbot, now used by the parish community, and the other on the inside which belongs to Genio Pontieri and cannot be visited. 

The façade is divided in three orders, on the rich main portal there is the statue of San Sisto. Inside, the church has three naves on a Latin cross plan; at its centre there is a dome covered on the outside by a lantern tower. The dome at the center of the transept at the entrance was frescoed by Bernardino Zacchetti. 

The two apses that close the main transept house the church monument to Margherita d’Austria and the Santa Barbara monumental chapel. The main transept is decorated with a trompe l’oeil of a coffered ceiling. 

For this church Raphael painted the "Madonna Sistina" that the Benedictine monks sold in 1754 to the king of Poland Augusto III, and is now exhibited at Gemaldegalerie in Dresden. 
The original was substituted by a copy made by P.A. Avanzini from Piacenza (1656-1733). The cloisters and the wooden choir, an interesting example of 16th century marquetry, are worth a visit.