Epidaurus was independent of Argos and not included in Argolis until the time of the Romans. With its supporting territory, it formed the small territory called Epidauria. Reputed to be founded by or named for the Argolid Epidaurus, and to be the birthplace of Apollo's son Asclepius the healer, Epidaurus was known for its sanctuary situated about five miles (8 km) from the town, as well as its theater, which is once again in use today. The cult of Asclepius at Epidaurus is attested in the 6th century BC, when the older hill-top sanctuary of Apollo Maleatas was no longer spacious enough.

The Asclepeion at Epidaurus was the most celebrated healing center of the Classical world, the place where ill people went in the hope of being cured. To find out the right cure for their ailments, they spent a night in the enkoimeteria, a big sleeping hall. In their dreams, the god himself would advise them what they had to do to regain their health. Within the sanctuary there was a guest house with 160 guest rooms. There are also mineral springs in the vicinity, which may have been used in healing.

Asclepius, the most important healer god of antiquity, brought prosperity to the sanctuary, which in the 4th and 3rd centuries BC embarked on an ambitious building program for enlarging and reconstruction of monumental buildings. Fame and prosperity continued throughout the Hellenistic period. After the destruction of Corinth in 146 BC Lucius Mummius visited the sanctuary and left two dedications there. In 87 BC, the sanctuary was looted by the Roman general Sulla. In 74 BC, a Roman garrison under Marcus Antonius Creticus had been installed in the city causing a lack of grain. Still, before 67 BC the sanctuary was plundered by pirates. In the 2nd century AD the sanctuary enjoyed a new upsurge under the Romans, but in AD 395 the Goths raided the sanctuary.

Even after the introduction of Christianity and the silencing of the oracles, the sanctuary at Epidaurus was still known as late as the mid 5th century as a Christian healing center.