After the destruction of Egnatia by the Ostrogoth king Totila in 545, its inhabitants fled to Monopoli, from which it derives its name as "only city". In the following centuries the area would be controlled by the Byzantines, Normans and Hohenstaufen, and was a starting point for naval Crusades expeditions. Later it was a fied under Angevine and Aragonese feudal lords.
In 1484 the city came under Venetian control and saw an economic upswing as a seaport on the Adriatic Sea as a base between Bari and Brindisi, as well as through trading its own agricultural goods. Under Spanish rule Monopoli became a free city in 1545. It became part of the kingdom of Italy in 1860.