The monastery was built around 356 on the burial site of Saint Anthony. Little is known about its earliest history. During the sixth and seventh centuries, many monks from the monasteries of Scetes went to the monastery of Saint Anthony, in order to escape the frequent attacks by the Bedouins and Berbers. The monastery itself was plundered a number of times by the Bedouins of the Eastern Desert, who partly destroyed it in the 11th century. It flourished between the 12th and 15th centuries, but was plundered again in 1454 by the Bedouins. In response to these attacks, a fortress-like structure was built around the monastery for its protection.