Before French colonisation, the Moulouya River was considered as the border between Regency of Algiers and the dynasties that controlled Morocco.

In medieval British pseudo-history, it was mentioned as a location along the route supposedly travelled by the ancestors of the Scotti, and by Brutus of Troy.

[5][6][7] The Moulouya River formed the eastern border of the kingdom of Mauretania since King Bocchus I, and more recently of the Rif Republic in the 1920s, a small part of Morocco containing important cities like Saïdia and Oujda lying to the east, between the Moulouya and the border with Algeria.

Until 1956 the river also formed the eastern border of the Spanish Protectorate of Morocco.

In August 2011 fish were killed by pollutants in the Moulouya River and local residents feared for their crops and livestock.