Meletius was made bishop of Sebaste in 357 and translated to the great see of Antioch in 360 by the Emperor Constantius II, who hoped that his irenic temperament would settle the long Antiochene contest between the Nicene and the moderate Arian parties. Within a month of his enthronement, Meletius preached in the cathedral of Antioch on Proverbs 8:22 ("The Lord created me at the beginning of His ways"), a text the Arianizing party had set as a test. He confessed the Nicene Faith without ambiguity.

The Arianizing party deposed and exiled him within weeks. He was three times deposed and three times restored over the next eighteen years, his see changing hands as the emperor changed: deposed under Constantius II in 360, restored under Julian in 362, deposed under Valens in 365, briefly restored under the western Valentinian in 367, deposed again under Valens, and finally restored under St. Theodosius the Great in 378 with the change of imperial policy after Adrianople.

Throughout his exiles he was supported by the Nicene community of Antioch (the Meletian community), among whom he had ordained the young John Chrysostom as deacon and presbyter. The schism in the Antiochene Church that arose during his absences (between his own followers and those of the rigorist Paulinus) was not finally healed until his successor, St. Flavian, named in the Synodical Letter of the Second Ecumenical Council.

When Theodosius summoned the Second Ecumenical Council to Constantinople in May of 381, Meletius came as the senior bishop of the Nicene Patriarchate of Antioch and presided over its opening sessions. He had been at the Council only a short time when he was struck by his last illness and reposed in Constantinople, full of years and of the long suffering by which the Antiochene see had been kept in the Nicene confession.

The Emperor gave him a public funeral. His body was taken back to Antioch in solemn procession, and Theodosius himself walked at the head of it as it left the imperial city. The presidency of the Council passed to St. Gregory the Theologian briefly, then to St. Nectarius.

What has happened to us, my brethren? Our father has gone away from us, leaving us his orphaned children. The shepherd has gone to lay down his life for the sheep, and we who are sheep are left as a flock without our shepherd. Yet we know that he is not gone from us in spirit; for the Faith which he taught us is among us still, and the prayers he prayed for us continue to be prayed in the Liturgy he handed down.

He was three times exiled, three times restored. He suffered everything that a bishop in his time could suffer, and he kept what he had received. He gave us the Faith of Nicaea, not in the words of dispute but in the practice of the Liturgy, that you yourselves bore on your shoulders to your homes in the hour of his exile, when the doors of his cathedral were nailed shut against his return.

Now he has returned to us, in the manner that is given a holy bishop to return: not in his own person, that we might see his face once more, but in the relics of his body, that we might honour them with the honour due to one through whom we have received the things that abide. Let us bury him with hymns and with thanksgivings, and let us learn from his life that the Faith he taught us is worth the long pain by which he kept it for us.

Bishop Meletius, herald of the Word, supreme primate, and friend of God: by the lessons of your wisdom you have enlightened the Church, and by the boldness of your confession you have torn down the impiety of heresy. Father, intercede with Christ our God to grant our souls the great mercy.