During the Middle Ages, Nice was marred by the military disasters of Italy. The city was allied with Pisa, which pitted it against Genoa. Both the French king and the Roman emperor tried to capture it, but it managed to sustain its political independence. The Counts of Provence seized Nice a number of times during the 13th and 14th Centuries. In 1388, the commune came under the protection of the Counts of Savoy.

Nice developed a significant naval capacity, so that it could cope with the pirates of the Mediterranean. The roads to the city were improved and its fortifications enhanced. During the battle between King Francis I of France and Holy Roman Emperor Charles V, the armies invading Provence wreaked havoc throughout the region. Famine and pestilence raged in the city for a few years. In 1538, the two monarchs concluded a ten-year peace treaty in Nice thanks to the mediation of Pope Paul III.

The combined forces of Francis I and Ottoman Admiral Khair ad Din Pasha Barbarossa attacked Nice in 1543. The history of Nice's patron saint is associated with this attack. When the army was preparing to invade, an ugly fat woman climbed a ladder and mooned the troops with the aim of scaring them off. The Turks retreated, and the woman was made patron saint. Eventually, however, the Nicois had to surrender. Barbarossa pillaged the city and took 2,500 captives. Sadly, Nice was hit by pestilence two more times during this century, in 1550 and 1580.