The establishment of the monastery is closely connected to the Julianist heresy, which spread in Egypt during the papacy of Pope Timothy III of Alexandria.

In reaction, those who did not follow the heresy obtained permission from the governor Aristomachus to erect new churches and monasteries, so that they could settle apart from the Julianists.

These new facilities were often built alongside the old ones, even keeping the same name but adding to it the word Theotokos, thus recognizing the significance of the incarnation, which the Julians seemed to minimize.

Towards the beginning of the eighth century AD, the monastery was sold to a group of wealthy Syriac merchants from Tikrit, who had settled in Cairo, for 12,000 dinars.

This made of the Syrian Monastery a prosperous and important facility, possessing many artistic treasures and a library rich in Syriac texts.

Towards the end of the fifteenth century, the Patriarch of Antioch visited the Syrian Monastery, granting it many privileges and donations, in order to restore it to its former glory.

In the seventeenth century, western travelers from France, Germany and England visited the monastery and reported that there were two churches, one for the Syrians and one for the Egyptians (Copts).

Near the church of the Holy Virgin, monks will continue to point out even today this tamarind, miraculously born from Ephrem's staff.

Between 1839 and 1851, the British Museum in London was able to purchase about five hundred Syriac manuscripts from the monastery's library, concerned not only with religious topics, but also with philosophy and literature.

The manuscripts found in the Syrian monastery inspired intense research on the Syriac language and culture, for until that time, many classical texts from Aristotle, Euclid, Archimedes, Hippocrates and Galen were known to Western scholars only in their thirteenth-century Latin translations.

Between 1991 and 1999, several segments of wall paintings layered on top of each other were uncovered in the Church of the Holy Virgin and the Chapel of the Forty-Nine Martyrs, dating from between the seventh and the thirteenth centuries.