He was born, probably in the third quarter of the 5th century, at Tahal, a village in the district of Beth Garmai east of the Tigris. He was thus by birth a subject of Persia, but all his active life of which we have any record was passed in the territory of the Byzantine Empire. The statements that he had been a slave and was never baptized appear to be malicious inventions of his theological opponents. He was educated at Edessa, perhaps in the famous "school of the Persians," which was afterwards (in 489) expelled from Edessa on account of its connexion with Nestorianism.
The years which followed the Council of Chalcedon (451) were a stormy period in the Syrian Church. Philoxenus soon attracted notice by his strenuous advocacy of Monophysite doctrine, and on the expulsion of Calandio (the orthodox patriarch of Antioch) in 485 was ordained bishop of Mabbog by his Monophysite successor Peter the Fuller (Barhebraeus, Chron. eccl. i. 183). It was probably during the earlier years of his episcopate that Philoxenus composed his thirteen homilies on the Christian life.
Later he devoted himself to the revision of the Syriac version of the Bible, and with the help of his chorepiscopus Polycarp produced in 508 the so-called Philoxenian version, which was in some sense the received Bible of the Monophysites during the 6th century. Meantime he continued his ecclesiastical activity, working as a bitter opponent of Flavian II, who had accepted the decrees of the Council of Chalcedon and was patriarch of Antioch from 498 to 512.
The Monophysites had the sympathy of the emperor Anastasius, and were finally successful in ousting Flavian in 512 and replacing him by their partisan Severus. Of Philoxenus's part in the struggle we possess not too trustworthy accounts by hostile writers, such as Theophanes and Theodorus Lector. We know that in 498 he was staying at Edessa; in or about 507, according to Theophanes, he was summoned by the emperor to Constantinople; and he finally presided at a synod at Sidon which was the means of procuring the replacement of Flavian by Severus. But the triumph was short-lived. Justin I, who succeeded Anastasius in 518, was less favourable to the party of Severus and Philoxenus, and in 519 they were both sentenced to banishment. Philoxenus was sent to Philippopolis in Thrace, and afterwards to Gangra in Paphlagonia, where he met his death by foul play in 523.
Apart from his redoubtable powers as a controversialist, Philoxenus deserves commemoration as a scholar, an elegant writer, and an exponent of practical Christianity. Of the chief monument of his scholarship - the Philoxenian version of the Bible - only the Gospels and certain portions of Isaiah are known to survive (see Wright, Syr. Lit. 14). It was an attempt to provide a more accurate rendering of the Septuagint than had hitherto existed in Syriac, and obtained recognition among the Monophysites until superseded by the still more literal renderings of the Old Testament by Paul of Telia and of the New Testament by Thomas of Harkel (both in 616-617), of which the latter at least was based on the work of Philoxenus.
There are also extant portions of commentaries on the Gospels from his pen. Of the excellence of his style and of his practical religious zeal we are able to judge from the thirteen homilies on the Christian life and character which have been edited and translated by E. A. Wallis Budge (London, 1894). In these he holds aloof for the most part from theological controversy, and treats in an admirable tone and spirit the themes of faith, simplicity, the fear of God, poverty, greed, abstinence and unchastity. His affinity with his earlier countryman Aphraates is manifest both in his choice of subjects and his manner of treatment. As his quotations from Scripture appear to be made from the Peshitta, he probably wrote the homilies before he embarked upon the Philoxenian version. Philoxenus wrote also many controversial works and some liturgical pieces. Many of his letters survive, and at least two have been edited. Several of his writings were translated into Arabic and Ethiopic.