The area also appears to have been part of the eastern cultural province of ancient Aksum: to this period dates back the foundation of the monastery of Debre Damo, which played a major role in Ethiopia's ecclesiastic history throughout the Middle Ages up to the modern times.

It remained the centre of prominent monasteries such as Gunda Gunde Maryam, which was established by the Stephanites (Abba Estifanos of Gwendagwende) during the 15th century.

[9] Agame had a major role to play in the political ascendancy of Tigray in Christian Ethiopia during the greater part of the first quarter of the 19th century.

One of the prominent warlords of northern Ethiopia, Dejazmatch Sabagadis Woldu, who ruled Tigray in the period 1822–31, had his power base in Agame.

During 1941–74 Agame existed as an awraja (in the province of Tigray), having five districts (woreda) under it: Gulo Makeda, Ganta Afshum, Subja Sase, Dallol and Kalatte Balaza.

[2] Topographically, the Agame area exhibits diverse physical features: mountain massifs, plains, plateaux, deep gorges and river valleys.

The local noble family had ruled over Agame from the "Era of the Princes" until the Derg deposed Emperor Haile Selassie in 1974.