Investigation of ancient stone huts found on the island indicate that it has been inhabited since the 3rd millennium BC. Thucydides identifies the original inhabitants as piratical Carians who were eventually expelled by King Minos of Crete. By the time of the Odyssey the island was already famous as the birthplace of the twin gods Apollo and Artemis. (Although there seems to be some confusion of Artemis' birthplace being either Delos or the island of Ortygia.) Indeed between 900 BC and AD 100, sacred Delos was a major cult centre, where Dionysus is also in evidence as well as the Titaness Leto, mother of the above-mentioned twin deities. Eventually acquiring Panhellenic religious significance, Delos was initially a religious pilgrimage for the Ionians.
A number of "purifications" were executed by the city-state of Athens in an attempt to render the island fit for the proper worship of the gods. The first took place in the 6th century BC, directed by the tyrant Pisistratus who ordered that all graves within sight of the temple be dug up and the bodies moved to another nearby island. In the 5th century, during the 6th year of the Peloponnesian war and under instruction from the Delphic Oracle, the entire island was purged of all dead bodies. It was then ordered that no one should be allowed to either die or give birth on the island due to its sacred importance and to preserve its neutrality in commerce, since no one could then claim ownership through inheritance. Immediately after this purification, the first quinquennial festival of the Delian games were celebrated there.
After the Persian Wars the island became the natural meeting-ground for the Delian League, founded in 478 BC, the congresses being held in the temple (a separate quarter was reserved for foreigners and the sanctuaries of foreign deities.) The League's common treasury was kept here as well until 454 BC when Pericles removed it to Athens.
The island had no productive capacity for food, fiber, or timber, with such being imported. Limited water was exploited with an extensive cistern and aqueduct system, wells, and sanitary drains. Various regions operated agoras (markets).
Strabo states that in 166 BC the Romans converted Delos into a free port, which was partially motivated by seeking to damage the trade of Rhodes, at the time the target of Roman hostility.
Roman traders came to purchase tens of thousands of slaves captured by the Cilician pirates or captured in the wars following the disintegration of the Seleucid Empire. It became the center of the slave trade, with the largest slave market in the larger region being maintained here.
The island was attacked in 88 BC by the troops of Mithridates VI of Pontus, a staunch enemy of Rome, who killed some 20,000 of the resident Romans. Another devastating attack was by pirates in 69 BC. Before the end of the 1st century BC, trade routes had changed; Delos was replaced by Puteoli as the chief focus of Italian trade with the East, and as a cult-centre too it entered a sharp decline.
Due to the above history, Delos - unlike other Greek islands - did not have an indigenous, self-supporting community of its own. As a result, in later times it became uninhabited.
Since 1872 the École française d'Athènes ("French School of Athens") has been excavating the island, the complex of buildings of which compares with those of Delphi and Olympia.