The Dorian invasion (1100–1000 BC) left three main Greek-speaking tribes: the Thesproti, the Chaones and the dominant Molossi. The marriage of Molossi princess Olympias to powerful Macedonian king Philip II brought conflict with emerging Rome. King Pyrrhus (319–272 BC) famously defeated the Romans at Ausculum, at a heavy cost; hence the concept of a ‘Pyrrhic victory'.

After the Roman Empire split in AD 395, Epiros was ruled from Constantinople. Centuries later, it became important after the 1204 Latin sack of Constantinople; Byzantine nobles escaping here established a key successor state. Eminent Byzantines again fled to Epiros' mountain fastnesses after the Ottomans conquered Constantinople in 1453.

Infamously linked with Epiros is 18th-century Albanian despot Ali Pasha, who ransacked much of Albania and western Greece, while wheeling and dealing with Turks, Brits and even Napoleon. Ali's remorseless mass killings and torture made him infamous, while Europeans were titillated by rumours of his harem of hundreds of women. Ottoman troops finally killed him in 1822, on Ioannina's lake island. Nevertheless, Ali had tacitly aided Greek freedom fighters elsewhere by wearing down and distracting the Turks.

Epiros was divided after 1912 when newly created Albania got a northern chunk. Mussolini’s 1940 invasion was repelled in Epiros, which became a communist resistance stronghold, first against the Nazis and then against the right-wing army in the Greek Civil War (1944–49). Although the communists lost, Epiros remains generally leftist.