His father Andronikos Dukas Angelos, a military leader in Asia Minor (c. 1122 – aft. 1185), married bef. 1155 Euphrosyne Kastamonitissa (c. 1125 – aft. 1195), was a son of Theodora Komnene (b. January 5, 1096/1097), the youngest daughter of Emperor Alexios I Komnenos and Eirene Doukaina, by her marriage c. 1120 to Konstantinos Angelos, Admiral of Sicily (c. 1085 – aft. July 1166), son of one Manolis Angelos from Philadelphia. Thus Isaac was a member of the extended imperial clan.
On September 11, 1185, during Andronikos' absence from the capital, the latter's lieutenant Stephanos Hagiochristophorites moved to arrest Isaac. Isaac killed Hagiochristophorites and took refuge in the church of Hagia Sophia. Andronikos, in some ways a capable ruler, was hated for his cruelty and his efforts to keep the aristocracy obedient. Isaac appealed to the populace, and a tumult arose which spread rapidly over the whole city. When Andronikos arrived he found that during his absence he had lost popular support, and that Isaac had been proclaimed emperor. Andronikos attempted to flee by boat but was apprehended. Isaac handed him over to the people of the City, and he was killed on September 12, 1185.
Isaac inaugurated his reign with a decisive victory over the Norman King of Sicily William II (on the banks of the Strymon, 7 September 1185), who had invaded the Balkans with 80,000 men and 200 ships towards the end of Andronicus I's reign. Elsewhere his policy was less successful. In late 1185, he sent a fleet of 80 galleys to liberate his brother Alexius III from Acre, but it was destroyed by the Normans of Sicily. He then sent a fleet of 70 ships, but it failed in its attempt to recover Cyprus from the rebellious noble Isaac Comnenus, thanks to Norman interference.
The oppressiveness of his taxes, increased to pay his armies and finance his marriage, resulted in the Vlach-Bulgarian Rebellion late in 1185. The rebellion led to the establishment of the Second Bulgarian Empire under the Asen dynasty. In 1187, Alexios Branas, the victor over the Normans, was sent against the rebels but turned his arms against his master, and attempted to seize Constantinople, only to be defeated and slain by Isaac's brother-in-law Conrad of Montferrat. Also in 1187, an agreement was made with Venice, in which the republic would provide 40-100 galleys at six months' notice in exchange for favorable trading concessions. As each Venetian galley was manned by 140 oarsmen, that means there were about 18,000 Venetians still in the empire even after Manuel I's arrests.
The emperor's attention was next demanded in the east, where several claimants to the throne successively rose and fell. 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; but he had no sooner crossed the border than Isaac, who had meanwhile sought an alliance with Saladin, threw every impediment in his way. In retaliation, Barbarossa's army occupied the city of Philippopolis and defeated a Byzantine army of 3,000 men that attempted to recapture the city. Thus compelled by force of arms, Isaac II was forced to fulfil his engagements in 1190. By 1196, Isaac II had allowed the once powerful Byzantine navy to decline to only 30 galleys.
The next five years were disturbed by continued warfare with Bulgaria, against which Isaac led several expeditions in person. In spite of their promising start, these ventures had little effect, and on one occasion in 1190 Isaac barely escaped with his life. While preparing for yet another offensive against Bulgaria in 1195, Alexios Angelos, the emperor's older brother, taking advantage of the latter's absence from camp on a hunting expedition, proclaimed himself emperor, and was readily recognised by the soldiers as Emperor Alexios III. Isaac was blinded and imprisoned in Constantinople.
Heavily beholden to the crusaders, Alexios IV was unable to meet his obligations and his vacillation caused him to lose the support of both his crusader allies and his subjects. At the end of January, 1204, the influential court official Alexios Doukas Mourtzouphlos took advantage of riots in the capital to imprison Alexios IV and seize the throne as Emperor Alexios V. At this point Isaac II died, allegedly of shock, while Alexios IV was strangled on January 28 or 29.
By his second wife, Margaret of Hungary (renamed Maria), Isaac II had two sons: