Octavian Caesar became the first Roman ruler of Egypt, reigning as the Emperor Augustus. Egypt became the granary of the Roman Empire and remained stable for about 30 years. The Romans, like their Greek predecessors, synthesized many Egyptian beliefs with their own, building temples at Dendara and Esna and Tranjan's kiosk at Philae. Hellenism remained a dominant cultural force and Alexandria continued to be a centre of Greek learning.

The Christian era began in Egypt with the spectacular biblical Flight of the Holy Family from Palestine. To this day the stages of the journey of Mary, Joseph and their infant Jesus are marked by shrines and churches. According to Coptic tradition, it was not until the arrival of Saint Mark that Christianity was established in Egypt during the reign of Nero. Saint Mark began preaching the gospel in about AD40 and established the Patriarchate of Alexandria in AD61.

The Egyptian Coptic Church expanded over three centuries in spite of Roman persecution of Christian converts throughout the Empire. In AD202 persecutions against Copts were initiated by the Roman authorities, continuing for nearly a century. In AD284, during the reign of the Emperor Diocletian, a bloody massacre of Coptic Christians took place from which the church has dated its calendar. Christianity was legalized and adopted as the official religion of the Roman Empire by the Emperor Constantine.

By the 3rd century AD the Roman Empire was in decline as a result of internal strife, famine and war, finally splitting into eastern and western empires. The eastern empire based in Constantinople became known as the Byzantine empire. The western empire remained centred in Rome.

The legalization of Christianity did not stop Roman persecution of the Coptic Christians because the Byzantine church was based upon fundamentally different beliefs than those of the Coptic Christian church which had adopted a Monophysite belief in the total divinity of Christ, as opposed to the Byzantine belief that Christ was both human and divine. The schism between the Byzantine and Coptic churches was never closed.

The Copts were formally excommunicated from the Orthodox Church at the Council of Chalcedon in AD451 and established their own Patriarchate at Alexandria. The fifth century was also a time when monasticism emerged and the Coptic monasteries of Saint Catherine, Saint Paul and Saint Anthony were established as well as those at Wadi Natrun and Sohaaj.
Apart from this doctrinal upheaval, the Byzantine rule over Egypt remained relatively stable until the coming of Islam.