The palace was built in 1593 on pre-existing medieval foundations, thanks to Francesco Grimaldi. Pieter Paul Rubens included it in “Palazzi di Genova”, published in Aversa in 1622, and documented it in a valuable manner through various engravings, such as that of the façade in the above-mentioned publication. It can be seen, from these engravings, how the two wings of the palace were initially connected by a loggia, which was then closed around the middle of the 17th century, and by a terrace on the second floor, where the mirror gallery was built in 1734. In addition, it is still possible to recover some fragments of the original frescoed decoration, in the form of architecture, which testify to the harmony between the external facades and the internal decoration of the main floor.
In 1958, Marquises Paolo and Franco Spinola donated their ancient residence, including paintings, furniture, ceramics, silverware, books and engravings, to the Italian State, from which the museum was effectively born. It should also be noted that the preservation of the building's original appearance was the only restriction for the donation. With the exclusion, however, of the last two floors, they suggested a different museum than the original one, from which the National Gallery of Liguria was inaugurated in 1993. The aim was to integrate the Spinola collection with the acquisitions of the State, in a complementary manner. Today, the Museum of the Royal Palace and the Palazzo Spinola National Gallery are part of the Museums of Genoa.