Threatened by Alfonso V of Aragon, the Doge of Genoa in 1458 handed the Republic over to the French, making it the Duchy of Genoa under the control of John of Anjou, a French royal governor. However, with support from Milan, Genoa revolted and the Republic was restored in 1461. The Milanese then changed sides, conquering Genoa in 1464 and holding it as a fief of the French crown. Between 1463–1478 and 1488–1499, Genoa was held by the Milanese House of Sforza. From 1499 to 1528, the Republic reached its nadir, being under nearly continual French occupation. The Spanish, with their intramural allies, the "old nobility" entrenched in the mountain fastnesses behind Genoa, captured the city on May 30, 1522, and subjected the city to a pillage. When the admiral Andrea Doria of the powerful Doria family allied with the Emperor Charles V to oust the French and restore Genoa's independence, a renewed prospect opened: 1528 marks the first loan from Genoese banks to Charles.

Under the ensuing economic recovery, many aristocratic Genoese families, such as the Balbi, Doria, Grimaldi, Pallavicini, and Serra, amassed tremendous fortunes. According to Felipe Fernandez-Armesto and others, the practices Genoa developed in the Mediterranean (such as chattel slavery) were crucial in the exploration and exploitation of the New World.