Kinet Höyük is situated between the former estuary of the Deliçay river and a small natural harbour, about 500 meters from the Mediterranean Sea. People moving from Cilicia to Syria had to pass through Issus before they climbed to the Syrian Gates or the Amanian Gates, two principal passes across the Amanus Mountains.

The site was already inhabited in the late Neolithic, about 5000 BCE, and remained occupied during the Bronze Age, the Hittite period (c.1400-c.1200 BCE), the Iron Age (c.1200-c.540 BCE), the Persian period (c.540-333 BCE), and the Hellenistic Age (333-c.50 BCE). Several strata can be discerned in the hill, which is now about twenty-six meter high.

Although the presence of some monumental architecture is certain, many more ordinary houses - usually made of mud brick- have been identified, and most finds are household items, which are not really unique. The popular figurines of the naked goddess holding her breasts have been found several times, in Bronze Age, Iron Age, and Hellenistic contexts, suggesting a continuous cult for an Aphrodite-like deity. There's a nice kiln from the sixth century, proving that artisans were living in the town. It is interesting to note that after the mid-sixth century, murex shells disappeared from the site, which suggests that the Persians did not appreciate a purple industry outside Phoenicia.

So far, no millstones have been found, which suggests that cereals were not processed in the city but in the country as Issus always was a real city and not an agricultural village. Fish, dairy products, and several types of meat were also part of the diet. Copper was imported from Cyprus; other ores were found in the Taurus. Transportation of these metals to Assyria and its successor empires (Babylonia and Persia) must have been the primary source of wealth.

Since 340 BCE, a clash between Macedonia and the Persian Empire was inevitable. In that year, the Macedonian king Philip laid siege to Perinthus, threatening the vital interests of Greece and Persia (clear transit through the Bosphorus and Hellespont). The Persians responded by sending troops to Europe. It was for the first time since Xerxes that the Persians intervened in the west, and the Macedonians considered this to be an unforgivable act of aggression. Philip first secured his rear; having provoked the Fourth Sacred War, he defeated the Greeks at Chaeronea (338 BCE) and forced them into the Corinthian League. Now, he was ready to strike east.

At about the same time, the Persian king Artaxerxes III Ochus died, leaving the Persian Empire without a strong successor. His son Artaxerxes IV Arses had to cope with revolts in Babylonia (Nidin-Bel), Egypt (Chababash), and Armenia (Artašata). For the Macedonians, everything was now ready for the attack - except that King Philip was assassinated in 336 BCE, more or less contemporary with the death of Arses and the accession of Artašata, who became known as Darius III Codomannus.

In 334, Philip's son and successor Alexander the Great invaded Asia, which was still poorly defended because of the Persian civil war. He defeated the local levies at the Granicus, which enabled him to conquer Anatolia. The only Persian force to offer resistance was the navy, commanded by Memnon and Pharnabazus, which consisted of Phoenician ships. To defeat the navy, the Macedonians decided to attack the Phoenician ports. In the autumn of 333 BCE, they entered Cilicia through the Cilician Gates.

The Macedonian force was commanded by Alexander's right-hand man Parmenion, who had occupied the site that is now known as Iskenderun. After reaching the capital of Cilicia, Tarsus, the Macedonian army had been divided: Alexander had attacked the mountain tribes of Rough Cilicia, opening a new line of communication, while Parmenion had occupied the Assyrian Gate to prevent a Persian invasion of Cilicia. When his scouts climbed to the pass, they saw the Persian army, and Parmenion sent messengers to Alexander, asking him to hurry to join him.

When Darius realised that not all Macedonians were on the other side of the Amanus Mountains, he decided to use the "Amanian Gate" or Bahçe Pass to cross the mountains and place his army between the two Macedonian armies at a town called Issus.

On 5 or 6 November 333 BCE, Alexander the Great's Macedonian army passed through the city. Several wounded soldiers were left behind. Not much later, the Persian king Darius III Codomannus took the city; on that same day, he was defeated by the Macedonians, several kilometres south of Issus. After his victory, Issus was called Nicopolis ("victory city"), and a new city was founded: Alexandria ad Issum (now İskenderun). Because the river on which Issus was founded was slowly silting up, Alexandria would eventually eclipse Issus, which appears to have been abandoned in c.50 BCE, perhaps after an earthquake.

Still, the site was not entirely forgotten. In 194 CE, the Roman emperor Septimius Severus defeated his rival Pescennius Niger near Issus, and a triumphal arch with a quadriga was erected near Nicopolis. The Sasanian king Shapur I claimed to have occupied the town in 260 CE. There must have been some settlement, which has not yet been identified by the excavators.