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.
