The construction of the prison was decided after the unification of Italy to remedy the inadequacy of the previous structures. The government purchased plots of land in the suburban area (what is now the area between Corso Magenta and Porta Ticinese), and hired engineer Francesco Lucca, who drew on the 18th-century model of the panopticon, designing a building with six arms of three storeys each. So-called 'walking roses' were built between the beams, divided into twenty sections, each for a single inmate, to prevent communication between them.

A medieval-style building was built on Piazza Filangieri, where the offices and the director's house were located. The work was completed by Antonio Cantalupi and the prison was inaugurated on 24 June 1879. It housed, among others, anarchist Gaetano Bresci (killer of Umberto I, King of Italy, in 1900) and the antifascist Antonio Gramsci (1927-1928).

After the German occupation in September 1943, the prison was largely subject to the jurisdiction of the SS. They directly managed three of its six sides, including side IV and VI for political prisoners, and side V for Jewish people (also known as the 'hanged men's circle' and the 'cursed side'). From that moment on, the prison functioned as a provincial concentration camp, operating as a collection point for the deportation of all Jews arrested in the largest northern cities such as Genoa and Turin, or those arrested at the border with Switzerland. Seven of the Jewish inmates in San Vittore died in prison, three from unknown causes.

Many workers from the industrial area of Sesto San Giovanni, who were deported for political reasons to the Nazi concentration camps, passed through San Vittore. Many resistance fighters were also imprisoned there, from Ferruccio Parri to Giuseppe Bacciagaluppi, as well as some who later become renowned such as Indro Montanelli and Mike Bongiorno.

There were also those who tried to make the prisoners' living conditions less harsh: 'like Sr Enrichetta Alfieri and Maria Peron. The latter managed to save some inmates from deportation and encouraged the escape of politicians. The final liberation of the prisoners, who themselves rose up on 25 April 1945, was carried out by the partisans of Matteotti Brigades.