The State of Epirus, also known as the Despotate of Epirus, was one of the States that emerged after the dissolution of the Byzantine Empire following the Fourth Crusade in 1204. Along with the Empire of Nicaea and the Empire of Trebizond, it is considered a legitimate continuation of the Byzantine Empire.

The founder of the State of Epirus and its first Despot (1205 - 1215) was Michael I Komnenos Doukas or Michael I Angelos. He is referred to as the “second Noah”, the one that saved the world from the “flood” of the Franks, and the city of Ioannina is described as the “ark of salvation”. The power vacuum created by the Partitio Romaniae , the treaty of partition of the Byzantine territories was filled by Michael I Angelos, who occupied a large area from the river Genoussos (modern name Shkumbin), south of Dyrrachion (Durrës in present-day Albania), to Nafpaktos. Venice recognized and legitimized Michael's power with the Treaty of 20 June 1210. However, two years later Michael expelled the Venetians from Dyrrachion and Corfu and reorganized his possessions as an independent principality. Epirus was the region that remained independent for a long time even after the reconquest of Constantinople in 1261, which marked the abolishment of the Latin Empire. Under the Despotate of Epirus, the city of Ioannina “was full of inhabitants, flourishing with wealth and boasting all other things”. “...after the fall of Megalopolis [sc. Constantinople]...” its refugees fled to the State of Epirus. Epirus became the new home of Greek refugees from Constantinople. Byzantine families from the former capital of the empire settled in the Ioannina Castle and founded a new class of settlers called “Kastrinoi Ioannites” (i.e., “Ioannites of the Castle”). This was an aristocracy of powerful, multiple branch families of Byzantine extraction that transformed the original townlet of Ioannina into an emerging city with economic and intellectual potential. Michael Doukas ensured the safe residence of the Constantinopolitan families within the Ioannina Castle by granting them a sufficient share of landed estates. His brother and successor, Theodore Doukas (c. 1180-1253), crowned Ruler of Epirus and Emperor of Thessaloniki (1224 - 1230), secured their rights by Royal Edict in 1227, despite the opposition of the native citizenry of the Castle. The rulers of Ioannina included the large landowners, who actively participated in the administration of the city. Among them were the Strategopoulos family, the Philanthropenos family, the Asparas family, the Melissinos family, etc. In 1318, the State of Epirus was incorporated into the Byzantine Empire, and in 1319 and 1321, the Chrysobulls of Emperor Andronikos II Palaiologos granted privileges to the inhabitants of Ioannina. A few years later, in 1330, the Count Palatine of Cephalonia and Zakynthos (1323-1325), Giovanni Orsini [Giovanni II Orsini, was anointed Despot of Epirus, as John Komnenos Doukas (1323-1335). Epirus was conquered by the Serbs in 1348 and Ioannina was ruled by Serbian Thomas II Prelubo or Preljubović or Thomas II Komnenos Prelubo Palaiologos, his wife being Maria Angelina Doukaina Palaiologina, until 1384. In 1380, the city of Ioannina’s first experience with the Ottomans is recorded with the first Ottoman invasions. The Ottomans operate in the area as allies of Preljubović. In 1385-1411, Esau or Esau de' Buondelmonti, originally from Florence, became "Despot" of Ioannina and, in 1411-1429, he was succeeded by Carlo I Tocco, Count Palatine of Cephalonia and Zakynthos (c. 1376-1429) and Duke of Lefkada, as “Despot” of Epirus (1411-1429) and Baron of Vostitsa.

The Kastrinoi receive a letter of exhortation/warning to admit surrender from Murad II [(Murad II, 1404-3 February 1451) مراد, Sultan of the Ottoman Empire (1421-1444 and 1446-1451)]. The letter (Amânnâme), written in Greek, is found in two transcriptions, the Meteor Codex and the Chronicle of Epirus. The second transcription is given below:

“Murad, King of East and West, to the Ioannites. You have been precisely convinced by the victories of mine and of my ancestors that God hath not placed any borders to my kingdom and, with his help, I have subdued all of the East and almost all of the West, that outside your mountains everyone hath kneeled before me. So I exhort you, before you taste the fatal ends of war, before you witness the blood of many innocent victims shed unjustly, to cede your city to me, if you would avoid its ruin and all others that befell the defiant and obstinate ones, cut down by my sword, or sold by my soldiers as captives in the East and West. This I promise you, if you worship me, faithful to your oath, I shall never expel you from your castle, and you shall not appear to be covetous and defiant to my kingship. Take heed lest, by dismissing my request, you have no longer any time to repent”.

At the same time, a similar letter was sent by Sinan Pasha [Sinan Pasha, Beylerbeyi of Rumeli, Grand Vizier, General and Representative of Sultan Murad II] to the Metropolitan of Ioannina (his name remains currently unknown) and the city's provosts. The letter of Sinan Pasha, known as the “Decree”, is a document which concerns the surrender of Ioannina and the special privileges set up for the inhabitants of the city, following the Ottoman subjugation, on 09 October 1430. It is preserved in two codices: the Sinaitic Codex, Gr 1208, sh.193v, of the 15th century; and the St. Petersburg Codex CCLVI, sh.23-24, of the 16th century.

“Decree which Sinan Pasha, vizier to Sultan Murad II, sent to Ioannina. From the chief of chiefs and ruler of all the West, Sinan Pasha's decree and greeting to His Eminence the Metropolitan of Ioannina and the honourable lords, to captain Strategopoulos and the captain's son, Sir Pavlos, and to Protostrator (stable master) Buisavon, and to Protasekritis (chief secretary) Stanitzis, and to the other lords of Ioannina, both great and minor. Know you that the great master hath sent us to receive Doukas’s place in his castle. And so we are commanded, that whatsoever castle and country shall bend the knee in good faith, let it hath no fear of neither evil, nor plunder nor any tribulation at all. And whatsoever castle and country shall not bend the knee, he hath ordered to seize them and burn them to the ground, as I did with Thessaloniki.

Wherefore I write and say unto you, that you bend the knee in good faith, and be not deceived with the words of the Franks, that they shall profit you nothing, but shall destroy you, as they have destroyed the Thessalonians. And therefore I swear you by the God of Heaven and earth, and by the prophet Muhammad, and by the seven Mus'haf (codices), and by the one hundred and twenty-four thousand prophets of God, and by my soul, and by my head, and by the sword that I gird, that you shall have no fear of neither captivity, nor taking of children, nor destroying of churches, nor misgadi (child levy) that we may perpetrate, but that your churches may toll as they used to. That the Metropolitan shall have the Roman judgment and all his ecclesiastical rights. That the lords that have timars (fiefs) shall have them again. That their bequests, their estates, and their possessions they shall keep them all, without any reason, and that we may provide for any other requests ye may request. If yοθ stubbornly resist and not bend the knee in good faith, know that as we hath pillaged Thessaloniki and destroyed the churches and lay waste and ruin to all things, so shall we also destroy you and your possessions, and God shall put judgment upon you.”

Becoming aware of the enormous growth and expansion rate of the Ottoman state, following the capture of Thessaloniki on March 29, 1430, and learning about the voluntary submission of approximately 500 families at Zagori, they decided to surrender consensually, with a single on one condition: to hand over the key of the city to Murad II himself so that the promised privileges could be agreed upon and secured. For this purpose, a special delegation was assembled, consisting of the lords of the Kastrinoi. Ioannina, although not the first, is the only city conquered by agreement for which we have the Ottoman document and its articles. Thus, on October 9, 1430, the diplomatic delegation of Ioannina handed over the keys of the city to Sultan Murad II. Among them are mentioned `Strategopoulos and his son Pavlos, Protomaistor (chief scholar) Buisavos, Protasekritis (senior secretary) Stanitzis, Lelyparas, Serbanos, Glykis, Papoulis etc. The meeting for the surrender of Ioannina took place outside Thessaloniki, at the present-day location of Kleidi. In return, a firman was granted by Sultan Murad II and a Hatt-ı şerîf (sacred edict) was signed which secured the self-government privileges—both religious and political— of the Ioannites.

The 16th century was a period of demographic growth without Muslim immigration. The urban population reached 7000, while the Christian community of Ioannina maintained their residences within the walls and their privileges. The Muslims lived outside the castle and comprised ten per cent of the local population. Despite this small percentage, Ottoman Ioannina grew. The town acquired a new look when the commercial and cultural centre moved outside the walls. It was the beginning of a new city extra muros with the active participation of the Christian community. The "Saray" neighbourhood stood across the western gate of the castle. It included the Government House, the Bajrakli Mosque, three mesjids (a place of worship without a minaret), and a hammam (public bathhouse). It was the new commercial, religious, and administrative centre.

The broader Behram Pasha neighbourhood was full of famous mansions like the residence of Nikolos Argyris. Nora Bielecka, niece of the French sub-consul in Ioannina, described them as "luxurious with roofs of clay tiles". In 1820, the area was destroyed during the siege of Ioannina by the Ottoman army attempting to capture Ali Pasha. The site is defined by Aneksartisias, Pavlou Mela, and Valaoritou streets. In 1611, the Christians of Ioannina lost their benefits after the failed revolt of Dionysios Philosophos or Skylosophos, the bishop of Larissa. As a result, they were gradually expelled from the castle and lost the privileges they had secured with the Ηatt-ı şerîf.

Many lost their fortunes, while others converted to Islam to keep their fiefs or part of their properties.

In 1613-1618, the Ottomans expelled all the Christians from the Castle and demolished most churches and monasteries that stood within the walls. Only Muslims and Jews are allowed to reside in the castle. The first Devshirme ("child levy" or "blood tax") also happened in 1622.

In 1635, Sultan Murad IV used the behaviour of the Christian sipahi from Epirus in the war against the Persians as an excuse to issue an edict depriving the timariots of the Castle and the broader area of privileges established more than two centuries ago. Many were forced to convert to Islam to safeguard their land and goods.