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.

Prior to the fifth century, Christianity in Ethiopia's Axum Empire was limited to the elite classes. However, the religion began spreading during the fifth century as Christian missionaries fled from the Roman Empire to Ethiopia due to a doctrinal disagreement with the Alexandrian church. In the fourth century, King Ezana declared the empire to be Christian and added crosses to the empire's flag and currency.

One effect of Axum's conversion to Christianity was conflict with the nearby Himyarite kingdom over their persecution of Christians, which led to decades of war between the two nations. Another effect was conflict with the Islamic Empire. Axum Christians were largely on friendly terms with Muslims, and they even offered shelter to Muhammad's followers shortly after his death. In the eighth century, however, the Islamic Empire attempted to conquer parts of Axum and convert it to Islam. This loss of land contributed to the decline of the Axum Empire.