The hospital's foundation was first laid on 29 June 1449, and it was built at the request of Dominic of Catalonia, a Dominican friar with the full support of the secular and ecclesiastical authority.

It was also called the Pietà Hospital to underline that the pietas, intended as love of neighbor, must be the guiding principle of the activity carried out within it.

The hospital emblem used at the time, which depicted the rising of Christ from the dead half-way up from the sarcophagus, had been used for centuries and is still being used today.

[10] In 2009, Johns Hopkins Medicine International signed a three-year agreement with Policlinico San Matteo to collaborate in the field of cardiac surgery, through exchange of talents and expertise.

[1][12] In collaboration with the University of Pavia, the hospital is able to procure 3D-printed patient-specific anatomical models in order to assist with general surgeries.