The fortress was built in 1542 by the Republic of Genoa on a promontory where in medieval times was the nucleus of Savona, by design of architect Giovanni Maria Olgiati. However, traces of pre-Roman, Roman and Byzantine presences in the site have been excavated in the past centuries, and are now on display in Savona's Archaeological Museum.
In the 17th century the fortress received bastions designed by the Spanish Royal engineer Domenico Sirena, and in the 18th century were added the commissar's, officers' and Sibilla palaces. In order to create space for the new structures, edifices of the medieval Savona, including its cathedral (built in th 9th century over a pagan temple), were demolished.
In 1746, in the course of the War of Austrian Succession, it was stormed by the Piedmontese grenadiers. In 1820, after the annexion of Liguria to Piedmont, it became a prison. During the Risorgimento, Italian patriot Giuseppe Mazzini was jailed in the Priamar Fortress.
The fortress, which could house up to 500 prisoners, remained Italy's main military prison until 1903, when its role was taken by the castle of Gaeta.