The first people of Axum to convert to Christianity were King Ezana and other members of the extended royal family, around the mid 4th century. The religion was spread to the general populace in the 5th century by Christian missionaries from the Eastern Roman Empire. There had likely already been a long influence of Judaism in the region, which helped facilitate a conversion to Christianity for many people. During its time, Axum became one of the major centers of the Eastern Orthodox Church.

The form of Coptic Christianity that took root in Axum proved to be very robust. Even after the fall of the Axum kingdom and the Muslim conquests in the 12th century, the religion survived and remained practiced. In fact, it still survives there to this day.

However, in the decades after Muhammad's death and the rapid spread of Islam, Axum became almost totally surrounded by Islamic states. This pushed Axum to the sidelines of commerce as most of the trade was conducted by Muslim merchants. They lost much of their control of the Red Sea and Nile River trade routes which hurt the local economy. This is one of the major reasons for the decline of Axum.