A son of Emperor Alexius I Comnenus and Irene Ducas, John kept an austere court and spent most of his reign with his troops. He canceled Venetian trading privileges granted by his father but was forced to restore them after the Venetians launched a fleet against him. He thwarted Pecheneg (Pechenegs), Hungarian, and Serbian threats during the 1120s, and in 1130 he allied himself with the German emperor Lothar II (Lothar II (or III)) (III) against the Norman king Roger II of Sicily.

In the later part of his reign John focused his activities on the East. In 1135 he defeated the Danishmend (Dānishmend dynasty) emirate of Melitene. Two years later he reconquered all of Cilicia from the kingdom of Lower Armenia and later forced Raymond of Poitiers, prince of Antioch, to recognize Byzantine suzerainty. Though John and Raymond formed an alliance against the Turkish Atabegs of Syria, their campaigns were not particularly successful. In 1143 John returned to press his claims to Antioch. He died following a hunting accident after naming his fourth son, Manuel I (Manuel I Comnenus), to succeed him.