The late 1st century AD writer Herennius Philo claimed that Antissa was named after the homonymous daughter of Macar, the legendary king of Lesbos.

[8] An alternative tradition attempted to etymologize Ἄντισσα (Antissa) as ἀντ’ Ἴσσα (ant' Issa), exploiting the meaning 'opposite to' of the Greek preposition ἀντί (anti).

Re-dividing toponyms to yield explanations for their origin was a common practice, and in this region we encounter it, for example, in the mythological tradition for Antandros in the Troad.

[10] This tradition appears to reflect the situation of Antissa's promontory, which was located on a low rise (elevation ~13 metres) jutting out to sea a short distance from its acropolis.

[11] The excavator of Antissa, Winnifred Lamb, noted that subsistence was a problem in the low-lying land between the promontory and the acropolis, and so the tradition may relate to an actual change in the landscape; alternatively, it could be the product of learned speculation.

Antissa joined the Mytilenaeans in their revolt from Athens in 428 BCE during the Peloponnesian war, and successfully defended itself against the Methymnaeans who attacked it.