Ephrem was born around the year 306 in the city of Nisibis, Mesopotamia, then recently acquired by Rome. Internal evidence from Ephrem's hymnody suggests that both his parents were part of the growing Christian community in the city, although later hagiographers wrote that his father was a pagan priest. Numerous languages were spoken in the Nisibis of Ephrem's day, mostly dialects of Aramaic. The Christian community used the Syriac dialect. The culture included pagan religions, Judaism and early Christian sects. Jacob, the second bishop of Nisibis, was appointed in 308, and Ephrem grew up under his leadership of the community. Jacob of Nisibis is recorded as a signatory at the First Council of Nicea in 325. Ephrem was baptized as a youth and almost certainly became a son of the covenant, an unusual form of Syriac proto-monasticism. Jacob appointed Ephrem as a teacher. He was ordained as a deacon either at his baptism or later. He began to compose hymns and write biblical commentaries as part of his educational office. In his hymns, he sometimes refers to himself as a "herdsman", to his bishop as the "shepherd", and to his community as a 'fold'. Ephrem is popularly credited as the founder of the School of Nisibis, which, in later centuries, was the center of learning of the Syriac Orthodox Church.
In 337, Emperor Constantine I, who had legalized and promoted the practice of Christianity in the Roman Empire, died. Seizing on this opportunity, Shapur II of Persia began a series of attacks into Roman North Mesopotamia. Nisibis was besieged in 338, 346 and 350. During the first siege, Ephrem credits Bishop Jacob as defending the city with his prayers. In the third siege, of 350, Shapur rerouted the River Mygdonius to undermine the walls of Nisibis. The Nisibenes quickly repaired the walls while the Persian elephant cavalry became bogged down in the wet ground. Ephrem celebrated what he saw as the miraculous salvation of the city in a hymn that portrayed Nisibis as being like Noah's Ark, floating to safety on the flood.
One important physical link to Ephrem's lifetime is the baptistery of Nisibis. The inscription tells that it was constructed under Bishop Vologeses in 359. In that year, Shapur attacked again. The cities around Nisibis were destroyed one by one, and their citizens killed or deported. Constantine II, was unable to respond; the campaign of Julian in 363 ended with his death in battle. His army elected Jovian as the new emperor, and to rescue his army, he was forced to surrender Nisibis to Persia (also in 363) and to permit the expulsion of the entire Christian population.
Ephrem, with the others, went first to Amida, eventually settling in Edessa in 363. Ephrem, in his late fifties, applied himself to ministry in his new church and seems to have continued his work as a teacher, perhaps in the School of Edessa. Edessa had always been at the heart of the Syriac-speaking world, and the city was full of rival philosophies and religions. Ephrem comments that orthodox Nicene Christians were simply called "Palutians" in Edessa, after a former bishop. Arians, Marcionites, Manichees, Bardaisanites and various Gnostic sects proclaimed themselves as the true church. In this confusion, Ephrem wrote a great number of hymns defending Nicene orthodoxy. A later Syriac writer, Jacob of Serug, wrote that Ephrem rehearsed all-female choirs to sing his hymns set to Syriac folk tunes in the forum of Edessa. After a ten-year residency in Edessa, in his sixties, Ephrem succumbed to the plague as he ministered to its victims. The most reliable date for his death is 9 June 373.