He was born in Thessalonika around 1300; his mother was a convert from Judaism. He entered monastic life, first at Mt Sinai, then at the Great Lavra on Mt Athos. The so-called "Hesychast controversy" was then raging, and St Philotheos became one of the firmest and most effective supporters of St Gregory Palamas (November 14) in his defense of Orthodoxy against western-inspired attacks on the doctrines of uncreated Grace and the possibility of true union with God. It was St Philotheos who drafted the Hagiorite Tome, the manifesto of the monks of Mt Athos setting forth how the Saints partake of the Divine and uncreated Light which the Apostles beheld at Christ's Transfiguration. In 1351, he took part in the "Hesychast Council" in Constantinople, and wrote its Acts. In 1354 he was made Patriarch of Constantinople; he stepped down after one year, but was recalled to the Patriarchal throne in 1364. He continued to be a zealous champion of undiluted Orthodoxy, writing treatises setting forth the theology of the Uncreated Energies of God and refuting the scholastic philosophy that was then infecting the Western church. Despite (or because of?) his uncompromising Orthodoxy, he always sought a true, rather than political, reconciliation with the West, and even worked to convene an Ecumenical Council to resolve the differences between the churches. This holy Patriarch was deposed in 1376 when the Emperor Andronicus IV came to the throne; he died in exile in 1379.

St Philotheos composed the Church's services to St Gregory Palamas. He is not listed in the Synaxaria, but is venerated as a Saint in the Greek church.