Saint Ambrose's 'New Basilica' was built on this site at the beginning of the 5th century, with an adjoining basilica added in 836.
When a fire damaged both buildings in 1075, they were later rebuilt as the Duomo.
The interior of the cathedral includes a huge number of monuments and artworks. These include:
- The Archbishop Alberto da Intimiano's sarcophagus, which is overlooked by a Crucifix in copper laminae (a replica).
- The sarcophagi of the archbishops Ottone Visconti and Giovanni Visconti, created by a Campionese master in the 14th century.
- The sarcophagus of Marco Carelli, who donated 35,000 ducati to accelerate the construction of the cathedral.
- The three magnificent altars by Pellegrino Pellegrini, which include the notable Federico Zuccari's Visit of St. Peter to St. Agatha jailed.
- In the right transept, the monument to Gian Giacomo Medici di Marignano, called "Medeghino", by Leone Leoni, and the adjacent Renaissance marble altar, decorated with gilt bronze statues.
- In front of the former mausoleum is the most renowned work of art of the cathedral, the St. Bartholomew statue by Marco D'Agrate.
- The presbytery is a late Renaissance masterpiece composing a choir, a Temple by Pellegrini, two pulpits with giant telamones covered in copper and bronze, and two large organs. Around the choir the two sacristies' portals, some frescoes and a fifteenth-century statue of Martin V by Jacopino da Tradate) can be seen.
- The transepts house the Trivulzio Candelabrum, which is in two pieces. The base (attributed to Nicolas of Verdun, 12th century), characterized by a fantastic ensemble of vines, vegetables and imaginary animals; and the stem, of the mid-16th century.
- In the left aisle, the Arcimboldi monument by Alessi and Romanesque figures depicting the Apostles in red marble and the neo-Classic baptistry by Pellegrini.
- A small red light bulb in the dome above the apse marks the spot where one of the nails from the Crucifixion of Christ has been placed.
- In November-December, in the days surrounding the birthdate of the San Carlo Borromeo, a series of large canvases, the Quadroni are exhibited along the nave.