Epirus is a region in northwestern Greece and Albania in a mountainous area between the Pindos and the Ionian Sea, with a rich coastal area, important for its connections with the West. Perhaps under Diocletian the province of Epirus was separated from Achaia, and by the time of the Verona List (produced between 328 and 337) it was divided into the provinces of Old Epirus (in the south) and New Epirus (in the north), both administratively part of the diocese of Moesia, later transferred to that of Macedonia. The capital of Old Epirus was Nikopolis and the capital of New Epirus was Dyrrachium. The area was plundered by the Vandals in the 5th century and many of its cities were fortified or refortified by Justinian I. Epirus was overrun by the Slavs in the late 6th-7th centuries and most of the cities disappeared. Restoration of Byzantine control came largely from the sea beginning in the 8th century. The themes of Dyrrachion and Nikopolis were created in the 9th century. By the end of the 12th century, many smaller territorial units were organized. In the 13th century the independent Despotate of Epirus was established after the fall of Constantinople in 1204 during the Fourth Crusade.

Although related to the Angelos dynasty in Constantinople, the early rulers of Epirus used the family names Komnenos and Doukas. The state was founded by Michael I Komnenos Doukas, who gained control of the entire northwestern coast of Greece and much of Thessaly. His ambitious brother Theodore Komnenos Doukas captured Ohrid in 1216. Theodore, who dreamed of recovering Constantinople, took Thessaloniki from the Latins in 1224 and was crowned as emperor, thus briefly setting himself up as a rival to the emperor of Nicaea. In 1242, however, Theodore's son John was forced by John III Vatatzes to substitute the title despotes for emperor, and in 1246 Thessaloniki was annexed by Nicaea. During the reign of Michael II Komnenos Doukas, Nicene forces temporarily conquered much of Epiros after the Battle of Pelagonia in 1259.

But Epirus recovered its independence by 1264 and continued to be ruled by Greek despotate until 1318, when it came under the control of the Italian Orsini family (1318-37). After a brief period of restoration of Greek rule, Epirus was occupied by the Serbs in 1348. In the late 14th century Ioannina returned to Italian control, first under the Florentine Esau Buondelmonti (1385-1411) and then under the house of Tocco, which also acquired Arta from the Albanians. Epirus was conquered by the Ottomans in the 15th century; Ioannina fell in 1430, Arta in 1449. Epirus was inhabited by Greeks, Slavs, Albanians, and Vlachs; Italians also penetrated the area. The ecclesiastical center of Epirus was Nikopolis until around 800; it was later succeeded by Naupaktos. Many early Christian churches have been found, especially at Nikopolis and along the coast, while later monuments are more common in the interior, especially around Arta.

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