Manuel was born on 2 January 1455 as the second son of Thomas Palaiologos, Despot of the Morea, and Catherine Zaccaria, the daughter of Centurione II Zaccaria, the last Prince of Achaea. After his uncle Constantine XI Palaiologos, the last Byzantine emperor, died defending Constantinople, the capital of the Byzantine Empire, on May 29, 1453, Manuel's family continued to live in the Morea as vassals of the Ottoman Sultan Mehmed II. But constant bickering between Thomas, who tried to rally support to restore the Byzantine Empire, and his brother Demetrios, who sided with the Ottomans, led the Sultan to invade the Morea in 1460; Thomas, Catherine and their children escaped to the Venetian-held island of Corfu. Thomas then left his family to go to Rome, where he was welcomed and provided for by Pope Pius II. Thomas maintained hope that he would one day recover his lands and when preparations were made for a crusade (which ultimately never took place), Thomas personally rode around Italy to drum up support.