Andronikos Palaiologos is a son of Emperor Manuel II Palaiologos and his wife Helena Dragaš.

His maternal grandfather was the Serb prince Constantine Dragaš.

His brothers include emperors John VIII Palaiologos and Constantine XI Palaiologos, as well as Theodore II Palaiologos, Demetrios Palaiologos and Thomas Palaiologos, who rule as despots in the Morea.

In childhood, Andronikos had survived the sickness that had killed his older brother Constantine and two sisters.

He has never recovered in full and will remain n poor health for the rest of his life, eventually developing leprosy.

When he was only eight years old his father had made him a despot (despotēs) and appointed him imperial representative in Thessalonica, where he succeeded his deceased cousin John VII Palaiologos.

As he was still a minor, for the first years of his rule there, until about 1415/1416, he was under the tutorship of the general Demetrios Laskaris Leontares.

After John VIII assumes control of the imperial government in 1421, the Empire faces an increasingly hostile Ottoman Empire.

Constantinople had been attacked in 1422 by the Ottomans.

Although the Turks had lifted the siege of Constantinople, Murad's armies had invaded Greece and in 1422–1423 subjected Thessalonica to a long blockade in 1422–1423.

Under siege, and increasingly unwell, Andronikos had begun diplomatic initiatives for the surrender of the city to the Republic of Venice.

Although he does not have the support of the whole of the population, and is opposed by the church, which mistrusts the Latins, these negotiations result in a Venetian force entering the city in 1423.

The handing over of Thessalonica to Venice contributes to the outbreak of the first in a series of wars between Venice and the Ottoman Empire.

Manuel II Palaiologos has retired to a monastery, where he die at seventy-five on June 21, 1425, leaving numerous literary works (many of which survive).

The well-educated emperor is the author of numerous works of varied character, including letters, poems, a Saint's Life, treatises on theology and rhetoric, and an epitaph for his brother Theodore I Palaiologos and a ‘mirror for prince’ (Latin: specula principum or rather, principum specula) for his son and heir John VIII.

This mirror of prince has special value, because it is the last sample of this literary genre bequeathed to us by the imperial Greeks.

John is sole emperor from July 1425, ruling the area immediately surrounding Constantinople, while his brothers govern remnants of the fragmented empire in the Greek Peloponnese and in the districts on the Black Sea.

The despots of Morea, Demetrios Palaiologos and Thomas Palaiologos, brothers of the last emperor, had failed to send him any aid, as Morea was reeling from a recent Ottoman attack.

Their own incompetence at rule leads to an Albanian-Greek revolt against them, when they invite in Ottoman troops to help them put down the revolt.

At this time, a number of leading Moreote Greeks and Albanians make private peace with Mehmed.

The two Greek despots of Morea surrender in 1460 to the Ottomans.

Thomas Palaiologos flees to Italy, his brother Demetrius to the Sultan's court.

Konstantinos Graitzas Palaiologos, commander of the imperial garrison at Salmenikon near Patras during the invasion of the Despotate of Morea by the forces of the Ottoman Empire in 1460, descends from an obscure branch of the Palaiologos family, but has shown far more valor than his distant relatives, the siblings and co-ruling Despotes Thomas Palaiologos and Demetrios Palaiologos.

Whereas the former had fled to Modon, Corfu, and finally Constantinople, and the latter had surrendered outright to the Sultan, Graitzas has maintained his position.

He holds his redoubt until July 1461, long after the surrender of his lords, at which point he is offered safe passage and a commission in the armed forces of the Republic of Venice.

Mani had remained under the control of the Despotate of Morea in May 1453 after the Ottoman Empire under Sultan Mehmet II took Constantinople.

Mehmet had occupied the Peloponnese in May 1460.

The Despotate of Morea had been ruled by the two brothers of Constantine XI, who had died defending Constantinople.

However, neither Demetrios Palaiologos nor Thomas Palaiologos had chosen to follow his example and defend the Peloponnese.

Thomas has instead fled to Italy, while Demetrios has sought refuge with Mehmet, to whom Helena Palaiologina, a daughter of Demetrios and Theodora Asanina, had been given in marriage.

Kladas, a Greek from Laconia, had in 1461 been granted lordship by Mehmet over Elos and Varvounia.

Mehmet had hoped that Kladas would defend Laconia from the Maniots.

During this time, Mani's population has grown as a result of an influx of refugees who have come from other areas of Greece.

Kladas turns against the Ottomans in 1463 and joins the Venetians, leading the Maniots against the Ottomans with Venetian aid.

The island of Lemnos had been added to the domain of the Gattilusi of Lesbos after the Fall of Constantinople to the Ottomans in 1453.

The Ottoman Sultan Mehmed II in 1456 had attacked and captured the Gattilusi domains in Thrace (Ainos and the islands of Samothrace and Imbros).

During the subsequent negotiations with the lord of Lesbos, Domenico Gattilusio, the Greek populace of Lemnos had risen up against Domenico's younger brother Niccolò Gattilusio, and submitted themselves to the Sultan, who had appointed a certain Hamza Bey as governor under the Bey of Gallipoli, Isma'il.

The island had been captured in 1457 by a Papal fleet.

Pope Callixtus III had hoped to establish a new military order on the island, which controls the exit of the Dardanelles, but nothing had come of it as Isma'il Bey soon recovered Lemnos for the Sultan.

Following the fall of the Despotate of the Morea in 1460, Sultan Mehmed II had given the proceeds from Lemnos to the last Despot, Demetrios Palaiologos.

During the First Ottoman–Venetian War, Lemnos and other former Gattilusi possessions had been seized in 1467 by the Venetians, but are returned to the Ottomans in 1479 under the Treaty of Constantinople.