In the beginning of the fifth century the political balances between the colonies of Magna Graecia changed again. Kroton, in fact, after having obliterated Sybaris (510 b.C.) regained control of most of the territory that had lost after the defeat in the battle of the Sagra river, and even extended it.

All of this damaged mainly Locri Epizephyrii. The Locrian polis, after having experienced what was one of the most flourishing periods of its history after the victory against Kroton, was now facing a very difficult situation that was harming the city, day by day, by losing control of larger parts of what was once its vast territory.

In fact, during these years, it seems that Locri Epizephyrii lost the direct control over all its sub-colonies and the cities that had integrated under its influence after the victory in the battle of the Sagra river, including the nearby Kaulon, which again fell under the control of Kroton.

Despite this, however, during the fifth century Kroton never constituted a real threat to Locri Epizephyrii.

The real threat to Locri Epizephyrii came from Rhegion which, once realized that Kroton while being always a threat to its territory at the moment didn't seem interested in waging war southwards, put its eyes on Locri Epizephyrii, at this moment in difficulty, to finally get rid of the geographical shackles that the same Locri Epizephyrii had imposed over Rhegion by preventing its expansion due to the close boundaries between the two cities.

In 477 b.C. the Rhegion's army led by Leophron, son of Anaxilas, lord of Rhegion, was about to attack Locri Epizephyrii. However the battle was avoided thanks to a strong diplomatic action of Hiero I, tyrant of Syracuse (to whom the Locrians had asked for help), who managed to dissuade Anaxilas from his intent.

From now on, the relationships between Locri and Syracuse became very close, giving rise to an alliance that will have an important place in Magna Graecia's history.

In the second half of the fifth century the great war between Athens and Sparta (the Peloponnesian war) inevitably affected also the western poleis, primarily because of the Athens' politics focused, in that period, to try to extend her influence (and her control) over the Greek colonies in Italy and Sicily. Control that tried to exercise even through the foundation of cities (as Thurii), the colonization of Neapolis, and some treaties, such as those with Rhegion, Leontini and other cities. Situations, these, which undoubtedly foreshadowed an Athenian military commitment in these lands much larger than anyone could have imagined by then.

The excuse to send her fleet in the West was offered to Athens by the request for help made by Leontini during the battle with Syracuse (427 b.C.). Rhegion immediately sided with Athens, becoming her base for naval operations in the West while, of course, Locri Epizephyrii along with the other cities loyal to the league of Sparta, took the field alongside the Syracusan ally.

This first phase of Athens' military operations in the West ended in 426 b.C. with a defeat near Locri Epizephyrii, which forced the Athenian army and fleet to a temporary retreat.

The following year Locri Epizephyrii and Syracuse, convinced that the control of the Strait was strategically crucial for the fate of the war, decided for a simultaneous attack by sea against Messene (the ancient Zancle, to which Anaxilas of Rhegion, once he took the control of the polis, imposed the name of his old home town) and occupied the city; at the same time, whilst the fleet was engaged in Messene, the Locrian army attacked the territory of Rhegion, in order to prevent a possible attempt of the polis' army to aid Messene, and withdrawing only after having laid waste on it.

Then there was a period of continuous clashes, by sea and by land, between the armies of Syracuse and of Locri Epizephyrii against their Athenians and Rhegion enemies in which there were ups and downs for both contenders; clashes that ended around 422 b.C.

After a brief period of calm, in 416 b.C., Athens tried again to conquer the Sicily, and to do this moved from Korkyra to Rhegion a fleet of 136 warships carrying an army of approximately 6500 men; during the winter of 415 b.C., since the Athenian fleet had received additional reinforcements, everything was ready for the battle that soon took place and that, at first, was in favor of the Athenians. In 414 b.C., in fact, the Athenian army and fleet laid siege to Syracuse.

The siege lasted for a long time but, thanks to its allies, and especially to a Spartan fleet, Syracuse was never conquered; on the contrary, during the following year, 413 b.C., the fleet of Syracuse and of her allies inflicted a heavy defeat to the Athenian one; defeat that also the Athenian army suffered by land in the following days. The siege was now broken and the Athenian fleet was so much in serious trouble that it suffered another heavy defeat; this time definitive and that forced, at first, a rapid retreat and, later on, the definitive surrender.

War was finally over and the main consequences it had for Locri Epizephyrii were, at least for the time being, to have rejected the danger that came from Rhegion and, above all, to have established a close relationship with Syracuse; a relationship that will be strengthened even more in the early fourth century b.C. with the marriage between Dionysius I, tyrant of Syracuse, and the daughter of an illustrious family of the Locrian nobility.