The origins of Cassano all'Ionio are very ancient, older than Sybaris. Archaeologists found early settlements dating back to the Neolithic, whose traces are in the extraordinary Caves of Sant'Angelo, which would point to Cassano being the first human settlement in Sibaritide and among the first in southern Italy. The first documented information of the toponym refers to a small town, Kossa, present in the hinterland of Sybaris in the 6th century BC, which, according to Hecataeus of Miletus, was one of the Enotri settlements.

In Greek times the main center of the area was Sybaris (Sibari is today a frazione of Cassano), on the Gulf of Taranto, between the rivers Crathis (Crati) and Sybaris (Coscile), which now meet 3 miles from the sea, but in ancient times had independent mouths; this was the oldest Greek colony in this region. It was an Achaean colony founded by Isus of Helice about 720 BC, but had among its settlers many Troezenians, who were ultimately expelled. The area was very fertile, and the city became large and wealthy, with a vast subject territory and diverse daughter colonies even on the Tyrrhenian Sea (Posidonia, Laus, Scidrus).

For magnificence and luxury the Sybarites were proverbial throughout Greece. Tension between the democrats and oligarchs led to the expulsion of the latter, who took refuge in Kroton and led a war to Sybaris, which was razed to the ground; the Krotonians turned the course of the Crathis to flow over its ruins in 510 BC.

In 444-443 BC there was the Panhellenic foundation of Thurii, from the name of a nearby spring. Later Thurii was occupied by the Lucans and gradually lost importance.

In 193 a.C. the Romans established there a colony, named Copia, which in 84 BC became a "municipium". A possible etymology for Cassano derives the toponym from a gens Cassia, or one Cassius, who received land in the area. During the 5th and 5th centuries AD Cassano began to decline for the swamping of the area, and a century later was completely abandoned.

In the Middle Ages the area passed under the domination of Longobards, Goths, Greeks, Saracens and Byzantines, and all of them left their signs in historical documents and place names.

In 576, under the Lombards, Cassano became a "gastaldato" of the Duchy of Benevento. In 951 it was sieged by Sultan Al Hassan, who spared it looting and destruction. In the second half of the 9th century AD Byzantine armies conquered the valley of the Crati river defeating the Lombards, and established a diocese.

In 1054 Cassano was occupied by the Normans and later by the Swabians. At Cassano there was a battle between Manfred of Sicily and Pietro Ruffo, vicar of Calabria, which ended with the victory of Manfred. In 1284, under the Anjous, Cassano became a fiefdom of one Icerio de Mignac, then was entrusted to several other feudal lords, including the Sanseverino (14th century) and the Prince of Bisignano, who gave it to the Genoese Francesco Serra in 1622. The Serra family enjoyed great nobility in Genoa, Spain, Sardinia and in the Kingdom of Naples.

At the turn of the 18th and 19th centuries Cassano was occupied by Napoleon's army: the French destroyed the Norman castle, whose foundations and remains of the city walls are still visible today. Cassano became then part of the Kingdom of the Two Sicilies and finally in 1861 was united to the Kingdom of Italy: in 1863 it assumed the name of "Cassano all'Ionio", to avoid confusione with a number of other Italian places named "Cassano".

Explorations undertaken by the Italian government in 1879 and 1887 discovered an extensive necropolis, some 8 miles to the west of the confluence of the two rivers, of the end of the first Iron age, known as that of Torre Mordillo, the contents of which are now preserved at Potenza, and another necropolis (probably of Thurii) of about 400 BC, consisting of tombs covered by "tumuli", in some of which gold plates with inscriptions in Greek characters were found.