Epiphanius was either born into a Romaniote Christian family or became a Christian in his youth. Either way, he was a Romaniote Jew who was born in the Old Yishuv in the small settlement of Besanduk, near Eleutheropolis (modern-day Beit Guvrin, Israel), and lived as a monk in Egypt, where he was educated and came into contact with Valentinian groups. He returned to Palestine around 333, when he was still a young man, and he founded a monastery at Ad nearby, which is often mentioned in the polemics of Jerome with Rufinus and John, Bishop of Jerusalem. He was ordained a priest, and lived and studied as superior of the monastery in Ad that he founded for thirty years and gained much skill and knowledge in that position. In that position he gained the ability to speak in several tongues, including Hebrew, Syriac, Egyptian, Greek, and Latin, and was called by Jerome on that account Pentaglossis ("Five tongued").
His reputation for learning prompted his nomination and consecration as Bishop of Salamis, Cyprus, in 365 or 367, a post which he held until his death. He was also the Metropolitan of the Church of Cyprus. He served as bishop for nearly forty years, as well as travelled widely to combat unorthodox beliefs. He was present at a synod in Antioch (376) where the Trinitarian questions were debated against the heresy of Apollinarianism. He upheld the position of Bishop Paulinus, who had the support of Rome, over that of Meletius of Antioch, who was supported by the Eastern Churches. In 382 he was present at the Council of Rome, again upholding the cause of Paulinus.