In 333 BC, Alexander the Great defeated the Persian forces at Issus. When he marched South and besieged Tire, the kings of Cyprus sent over 220 ships to help stop the invasion of the city.

Alexander continued his campaign in Egypt, where he founded the city of Alexandria, before marching Eastward to the Indus. However, he died at the age of 33 and the new independence enjoyed by Cyprus and its city kingdoms was short-lived.

With his untimely death he left no heirs, although his wife was pregnant with a son. Fighting broke out between the Macedonian generals who fought to succeed Alexander. Cyprus came under the control of Ptolemy, the Sitrap of Egypt, who established a protectorate over Cyprus.

The city kingdoms, which had enjoyed relative autonomy under the Assyrians and the Persians, passed under the central government of Paphos. Cultural and religious institutions remained largely untouched by the Ptolemies, although the Greek alphabet had gradually been introduced in the meantime.

The importance of Cyprus as a maritime and commercial centre at this time is symbolized by the sinking of a Greek merchant ship, recovered by archaeologists off the North coast, and now preserved with its contents in the castle of Kyrenia.

By 58 BC, however, the dynasty founded by Ptolemy had become weak, and when a Roman officer was insulted by the king of Cyprus, this episode was used as an excuse to annex the island, which became a province of the Roman Empire.