The toponym would, then, be of Messapic origin, and related to the semantic field of 'horses', also seen in Illyrian theonym Iuppiter Menzanas and Albanian mëz-i 'foal'.

Archidamus III, king of Sparta, fell beneath its walls in 338 BC, while leading the army of the latter (Manduria is also referred to as "Mandonion" in works by the Greek and Roman historian Plutarch).

The modern city is close to the site of the ancient Manduria, considerable remains of the defences of which can still be seen; they consisted of a double line of wall built of rectangular blocks of stone, without mortar, and with a broad ditch in front.

The symbol of the city is a well with an almond tree growing from the center, which was mentioned by the Roman author Pliny the Elder in Naturalis Historia, a work published in the 1st century AD.

The well (named Fonte Pliniano after Pliny the Elder) can still be seen today exactly as it was described some 2,000 years ago, with the almond tree still rising out of the center.