Traces of human life that have been found come from the end of Neolithic Era (4.000-3.000 BC.). The first habitants of the island came from Asia Minor and were relatives with pre-Hellenic people who lived in Crete and other Greek islands (Kares etc.).

The primitive Neolithic civilization of Karpathos continued to the 3rd millennium, but around 2.000 BC. Minoan colonists from Crete brought economic and cultural development to the island. During Neoanactoric Era of Crete (around 1.700-1.450 BC.) - known also as the Era of Minoan Sea Domination and Colonism, Karpathos seems to have had definite Minoan characteristics. It had a large population and was culturally and economically developed.

The historian Diodoros Sikeliotis mentions that the first people of Karpathos were the first people who were sent by Minoas to Karpathos as colonists during the period of the Minoan Sea Domination. After them came colonists from Argos (apparently Mycenaean) with Ioklos, son of Demoleon, as leader. Homer, as well as the archaeological references, confirm the presence of Achaians (Greek Mycenaeans) on the island, despite the fact that the Minoan character of the civilization existed till the end of the Bronze Era. Karpathos took part in the Trojan War under the orders of Feidipos and Antifos.
There are no findings from the end of the Bronze Era till the Archaic Period.

It seems that in those times Dorian population dominated and the four cities which Stravon mentions may have been built from the Archaic times or even from previous years. During the Classic and Hellenistic times Karpathos seems to have had cultural and economic progress. This was due to a great extent to the economic and cultural relations with Rhodes, especially with Lindos.

The major village of those times was apparently Karpathos which was possibly situated in the area of Aperi. This village as it is known today seemed to be the capital of the island the following years. It continued to be during the Turks domination till 1892 A.D. when capital of the island became Pigadia, the seaport of the city of Karpathos in antiquity, and in those times was called "Poseidion".

The other three cities were Arkesia, near the village of Arkasa, Vrykous, (today it is called Vroukounta, in the northwest of Karpathos) and Nisiros which possibly was situated on the island of Saria. Saria in ancient times was an independent island and was called Saros.

After 478 B.C. Karpathos became member of the 1st Athenian Alliance as was proven from the taxes the members used to pay. In 404 B.C., the end of the Peloponesean War, the island was subdued to the Spartans, but after the sea battle of Knidos (394 B.C.) came under the rule of the Athenians and became member of the 2nd Athenian Alliance.

During the Hellenistic Period a great part of the island was under the rule of the Rhodean State, in other words the Lindian State.