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Egyptian Christians believe that the Patriarchate of Alexandria was founded by Mark the Evangelist around 33, but little is known about how Christianity entered Egypt. The historian Helmut Koester has suggested, with some evidence, that originally the Christians in Egypt were predominantly influenced by gnosticism until the efforts of Demetrius of Alexandria gradually brought the beliefs of the majority into harmony with the rest of Christianity. While the collective embarrassment over their heretical origins would explain the lack of details for the first centuries of Christianity in Egypt, there are too many gaps in the history of Roman times to claim that our ignorance in this situation is a special case.

Nevertheless, by 200 it is clear that Alexandria was one of the great Christian centres. The Christian apologists Clement of Alexandria and Origen both lived part or all of their lives in that city, where they wrote, taught, and debated.

With the Edict of Milan in 312, Constantine I ended the persecution of Christians, and in 324 he made Christianity the religion of the Empire. Over the course of the 4th century, paganism gradually lost its following, as the poet Palladius bitterly noted. It lingered underground for many decades: the final edict against paganism was issued in 390, but graffiti at Philae in Upper Egypt proves worship of Isis persisted at its temples into the 5th century. Many Egyptian Jews also became Christians, but many others refused to do so, leaving them as the only sizeable religious minority in a Christian country.

No sooner had the Egyptian Church achieved freedom and supremacy, however, than it became subject to schism and prolonged conflict which at times descended into civil war. Alexandria became the centre of the first great split in the Christian world, between the Arians, named for the Alexandrian priest Arius, and orthodoxy, represented by Athanasius, who became Archbishop of Alexandria in 326 after the First Council of Nicaea rejected Arius's views. The Arian controversy caused years of riots and rebellions throughout most of the fourth century. In the course of one of these, the great temple of Serapis, the stronghold of paganism, was destroyed. Athanasius was alternately expelled from Alexandria and reinstated as its Archbishop between five and seven times.

It was never easy to impose religious orthodoxy on Egypt, a country with an ancient tradition of religious speculation. Not only did Arianism flourish there, but other heresies, such as Gnosticism and Manichaeism, either native or imported, found many followers. Another religious development in Egypt was the monasticism of the Desert Fathers, who renounced the material world in order to live a life of poverty in devotion to the Church. Egyptian Christians took up monasticism with such enthusiasm that the Emperor Valens had to restrict the number of men who could become monks. Egypt exported monasticism to the rest of the Christian world. Another development of this period was the development of Coptic, a form of the Ancient Egyptian language written with the Greek alphabet supplemented by several signs to represent sounds present in Egyptian which were not present in Greek. Coptic was invented as a means to ensure correct pronunciation of magical words and names in "pagan" texts, the so-called Greek Magical Papyri. Coptic was soon adopted by early Christians to spread the word of the gospel to native Egyptians and it became the liturgical language of Egyptian Christianity and remains so to this day.