The so-called despotate of Epirus (ruled by a despotēs, or lord), which usually included Cephallenia (Kefallinía), was established by Michael I Komnenos Doukas, who established effective control after 1204 over northwestern Greece and a considerable part of Thessaly. His brother and successor Theodore was able to retake Thessalonica from the Latins in 1224, where he was crowned as emperor, thus challenging the emperor of Nicaea, who claimed imperial rule. However, in 1242 the Nicaean ruler John III Ducas Vatatzes compelled Theodore’s son and successor John to abandon the title of emperor, and by 1246 Thessalonica was under Nicaean rule. In 1259 much of Epirus came under Nicaean control, but this was lost by 1264. Thereafter Epirus continued to be ruled by independent despots (despotai) until 1318. Its sheltered geographic position, between the spine of the Pindus mountain range and the Adriatic Sea, facilitated a degree of political separatism and independence from Constantinople until the Ottoman conquest. The Byzantine emperors, however, always insisted on their rights to confer the title of despotēs, and for much of the 14th and 15th centuries they regarded the rulers of Epirus as rebels.

From 1318 until 1337 Epirus was ruled by the Italian Orsini family, and after a short Greek recovery it was taken by the Serbs in 1348, and Ioánnina and Árta were its main political centres. From 1366 to 1384 Ioánnina was ruled by Thomas Komnenos Palaeologus, also known as Preljubovič, the son of the caesar Gregory Preljub, who had been the Serbian governor of Thessaly under Stefan Uroš IV Dušan. He was able to assert Serbian control over northern Epirus and fought with the Albanian lords of Árta (Ghin Bua Spata and Peter Ljoša) in the south, eventually defeating them with the aid of the Ottomans. In 1382 his title of despotēs was confirmed by the Byzantine emperor at Constantinople. He was assassinated late in 1384, probably by members of the local nobility who objected to his rule. His widow, the Byzantine Maria Angelina Doukaina Palaiologina, married the Italian nobleman Esau Buondelmonti, who ruled as despotēs until about 1411. Thereafter the despotate came under the Italian house of Tocco, whose rulers were able to recover Árta from the Albanians. But in 1430 the Ottomans took Ioánnina and in 1449 they captured Árta, and, thus, Epirus became part of the Ottoman Empire. Cephallenia was taken in 1479, but Venice seized it in 1500.

Thessaly and surrounding regions

The political history of the other regions of Greece during this period is no less complex. Thessaly was ruled in its eastern parts by the Franks after 1204, while the western regions were disputed by the rulers of Epirus and Nicaea. About 1267 John I Doukas established himself as an independent ruler, with the Byzantine title sebastokrator, at Neopatras, but in expanding his control eastward he came into conflict with Michael VIII, whose attacks he repelled with the assistance of the dukes of Athens and Charles I of Anjou. Venetian support, the result of a favourable trading relationship (Thessaly exported agricultural produce), helped maintain Thessalian independence until the arrival in 1309 of the Catalan Grand Company. That band of Spanish mercenaries, who originally had been hired by Andronicus II to fight the Seljuqs in Anatolia turned against imperial authority and established themselves in the Gallipoli peninsula. From there they moved into Greece through Thrace and Macedonia, which they plundered, and from 1318 onward they occupied the southern districts of Thessaly. The northern regions remained independent under the ruler Stephen Gabrielopoulos until 1332, and then they were taken by John II Orsini of Epirus. In 1335 Thessaly was retaken by the Byzantine Empire, and from 1348 it acknowledged the overlordship of the Serbian ruler Stefan Dušan. After his death (1355) the self-styled emperor Symeon Uroš, despotēs of Epirus and Akarnania, was able to seize control of both Epirus and Thessaly and rule independently following the death of Nikephoros II in 1358/59. He was succeeded by his son John, who adopted the monastic life in 1373. The caesar Alexios Angelos Philanthropenos took control, governing as a vassal of the Byzantine emperor John V, but in 1393 the conquest of Thessaly by Ottoman forces put an end to its independence.