Founded in the 11th century BC by the sea-going Phoenicans, the city was known as Hadrumetum, and is one of the oldest surviving ports in the Western Mediterranean. During the Second Punic War in the 1st century BC the city was used as a military stronghold by Hannibal the Great of Carthage, but in the Third Punic War the city allied itself with Rome.

Thus it was spared the destruction that the Romans brought to various Carthaginian and other North African centers. However, the city did side with Pompeii during the Roman Civil War, and the victorious Julius Caesar imposed heavy taxation on Hadrumetum as a result. Following the establishment of Roman Empire the city fared well and became an important center of commerce in North Africa during the era of Pax Romana. 

With the decline and fall of the Roman Empire in the 6th century, the city was taken first by the Vandals and then retaken by the Eastern Roman Empire or Byzantines who controlled the city until the end of the 7th century. During this era it was first renamed Hunerikopolis by the Vandals and later Justinianopolis, after the ruling Eastern Roman Emperor at the time.

The Muslim Arabs conquered the city in the 7th century, and with it the name was changed to Susa, and it became a prosperous seaport during the Aghlabid Dynasty, which occupied and controlled Northern Africa for several centuries.

The Normans briefly captured the city in the 12th century, before it passed to Spanish control for the next several hundred years. It faced various threats from Corsair pirates and attacks by the Venetian Kingdom, until in the 19th century, with the rest of Tunisia, the city finally came under the control of the French who had once again renamed it, by the name it retains to this day: Sousse.

Today Sousse retains its North African Arabian characteristics and charms, while earlier influences are abundantly present as well.