Contemporary sources recall that the so-called Basilica Portiana resisted the efforts of St Ambrose to wrest it from the Arians.

Towards the middle of the eleventh century, the open space behind the basilica, called Vetra, was used as the place of executions: this practice continued until 1840 and was reported, among others, by Alessandro Manzoni in the history of the infamous column.

Subsequently, during the age of the Renaissance, especially after the 1154 destruction of the other Ancient Roman structures by Emperor Barbarossa, the temple was an example of the classical architectural canons admired by humanists, and studied by architects and artists such as Bramante, Leonardo, and Giuliano da Sangallo.

During the reconstruction, a miracle occurred, one predicted by Archbishop Carlo Borromeo: one year after his death in 1585, a sick woman was cured in front of the icon of the Madonna del Latte, displayed on the Piazza della Vetra.

The basilica, perhaps to avoid the unstable and marshy ground, was built on an artificial hill not far from the walls, along the Via Ticinensis, the main access route to the city, and not far from the Imperial Palace and the amphitheatre, from which were taken some of the materials used in constructing the temple itself.

The complex was surrounded by various waterways, coming together to form the Vettabbia, the canal that takes away the waters of Milan, which still flow towards the agricultural areas to the south of the city.

This consisted of a square hall inscribed as a building with four apses, whose semicircular hollows overhung by semi-cupolas were articulated by four columns.

Of the two side buildings, the smaller was in the east, opposite the entrance: a chapel in the shape of a Greek cross, later on octagonal, dedicated to St Hippolytus.

The larger building was to the south, having the function of the imperial mausoleum: tradition attributing its foundation to Galla Placidia, which is why the sacellum took on the name of the chapel of the Queen.

Perhaps in this period, when Roman imperial authority in Italy had diminished, the mausoleum to the south of the basilica was transformed into a chapel dedicated to St Genesius the martyr.

In the tenth century, probably in the Ottonian era, reconstruction took place possibly involving the participation of a Byzantine workforce who had retained knowledge of the classical techniques of construction and decoration.

In 1894, the engineer and architect Cesare Nava built a vestibule in front of the church, consisting of three ionic arches in stone-like cement.

The fresco The Rediscovery of the corpse of Saint Aquilinus of Cologne, by Carlo Urbino, decorates the wall behind the main altar in the Sant'Aquilino chapel.

The square facing the basilica features the so-called "Colonne di San Lorenzo" (Columns of St. Lawrence), one of the few remains of the Roman "Mediolanum", dating from the 3rd century AD and probably belonging to the large baths built by the emperor Maximian.

Previously the area was occupied by a channel or a lake (probably with a port), while later it was used in public executions, one of which is recounted in Alessandro Manzoni's Storia della Colonna Infame.