In a 1185 revolt against the Emperor Andronikos Komnenos, Isaac seized power and rose to the Byzantine throne, establishing the Angelos family as the new imperial dynasty.

Niketas Choniates described Isaac's physical appearance: "He had a ruddy complexion and red hair, was of average height and robust in body".

Isaac inaugurated his reign with a decisive victory over the Norman[6] King of Sicily, William II, at the Battle of Demetritzes on 7 November 1185.

This fleet was misinterpreted by many in the Holy Land as naval support for the Muslim offensive in accordance with Isaac's alliance with Saladin.

[8][9] Isaac's administration was dominated by two figures: his maternal uncle Theodore Kastamonites, who became virtually a co-emperor and handled all civil government until his death in 1193; and his replacement, Constantine Mesopotamites, who acquired even more influence over the emperor.

In 1187 Alexios Branas, the victor over the Normans, was sent against the Bulgarians but turned his arms against his master and attempted to seize Constantinople, only to be defeated and slain[6] by Isaac's brother-in-law Conrad of Montferrat.

Also in 1187 an agreement was made with Venice, in which the Venetian Republic would provide between 40 and 100 galleys at six months' notice in exchange for favorable trading concessions.

In 1189 the Holy Roman Emperor Frederick I Barbarossa sought and obtained permission to lead his troops on the Third Crusade through the Byzantine Empire.

The Byzantine army was victorious in the battle at South Morava (autumn 1191), that led to the recovery of Niš and the consequent peace treaty.

[6] In 1203, after eight years of captivity, Isaac II was raised from the dungeon to the throne once more[6] after the arrival of the Fourth Crusade and the flight of Alexios III from the capital.

Both his mind and body had been enfeebled by his blindness and confinement,[6] and his son Alexios IV Angelos was associated on the throne as the effective monarch.

[6] Surrounded by a crowd of slaves, mistresses, and flatterers, he permitted his empire to be administered by unworthy favourites, while he squandered the money wrung from his provinces on costly buildings and expensive gifts to the churches of his metropolis.

In an Italian edition of the chronicle of Nicetas Choniates "Greatness and catastrophe of Byzantium" can be found an interesting note to the XIV Book.

The names of Isaac II's first wife and eldest daughter, unknown from Byzantine sources, are found in an obituary in the Cathedral of Speyer, the pantheon of German kings.

Here, the wife of Philip of Swabia is said to be the daughter of Isaac and Irene (there is reference to the following article: R. Hiestand, Die erste Ehe Isaaks II.