Following their victory at the Battle of Heliopolis in July 640, and the subsequent capitulation of Alexandria in November 641, Arab troops had taken over what was the Roman province of Egypt. The newly installed Byzantine Emperor Constans II was determined to retake the land, and ordered a large fleet to carry troops to Alexandria. These troops, under Manuel, took the city by surprise from its small Arab garrison towards the end of 645 in an amphibious attack. In 645, the Byzantine thus temporarily won Alexandria back. Amr at the time might have been in Mecca, and was quickly recalled to take command of the Arab forces in Egypt.

The battle took place at the small fortified town of Nikiou, about two-thirds of the way from Alexandria to Fustat, with the Arab forces numbering around 15,000, against a smaller Byzantine force. The Arabs prevailed, and the Byzantine forces retreated in disarray, back to Alexandria. Although the Byzantines closed the gates against the pursuing Arabs, the city of Alexandria eventually fell to the Arabs, who stormed the city sometime in the summer of that year.

The permanent loss of the Egypt left the Byzantine Empire without an irreplaceable source of food and money. The new center for manpower and revenue shifts to Anatolia. The loss of Egypt and Syria, followed later by the conquest of the Exarchate of Africa also meant that the Mediterranean, long a "Roman lake", was now contested between two powers: the Muslim Caliphate and the Byzantines.