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.