Born in
Constantinople, John Kantakouzenos was the son of
Michael Kantakouzenos, governor of the
Morea;
Donald Nicol speculates that he may have been born after his father's death and raised as an only child. Through his mother Theodora Palaiologina Angelina, he was related to the then-reigning house of
Palaiologos. He was also related to the imperial dynasty through his wife
Irene Asanina, a second cousin of Emperor
Andronikos III Palaiologos. Kantakouzenos became a close friend to Andronikos III and was one of his principal supporters in Andronikos's
struggle against his grandfather,
Andronikos II Palaiologos. On the accession of Andronikos III in 1328, he was entrusted with the supreme administration of affairs and served as
grand domestic throughout his reign. He was named regent to Andronikos's successor, the 9-year-old
John V, upon the emperor's death in June 1341. Kantakouzenos apparently began with no imperial ambitions of his own, having refused several times to be crowned
co-emperor by Andronikos III. After the death of the emperor, Kantakouzenos again refused to take the throne, insisting on the legitimacy of John V's claim and contenting himself with overseeing the empire's administration until the boy came of age: according to the history written by John VI himself. Whether he would have remained loyal is unknowable but, despite his professed devotion to John V and his mother
Anna, she came to suspect him of treason. His close friendship with the late emperor and power over his successor had aroused the jealousy of his former protégés, Patriarch
John XIV of Constantinople and
Alexios Apokaukos; after a series of failed attempts, they succeeded in overthrowing his regency in September 1341 while he was out of the capital readying an army against the
Crusader principalities that still held parts of the
Peloponnesus. He attempted to negotiate with the usurpers, but this was rebuffed and his army was ordered to disband. Further, his relatives in Constantinople were driven into exile or imprisoned, with their property confiscated by the new regents. His mother Theodora died owing to the mistreatment she suffered while under house arrest. His army ignored the new regents' orders and proclaimed Kantakouzenos emperor at
Didymoteichon in
Thrace as John VI. He accepted this, while continuing to style himself as the junior ruler to John V. ==Civil war==