Alexios's son John II Komnenos succeeded him in 1118 and ruled until 1143. John was a pious and dedicated Emperor who was determined to undo the damage to the empire suffered at the Battle of Manzikert, half a century earlier. Famed for his piety and his remarkably mild and just reign, John was an exceptional example of a moral ruler at a time when cruelty was the norm. For this reason, he has been called the Byzantine Marcus Aurelius.

During his twenty-five year reign, John made alliances with the Holy Roman Empire in the West and decisively defeated the Pechenegs at the Battle of Beroia. He thwarted Hungarian and Serbian threats during the 1120s, and in 1130 he allied himself with the German emperor Lothair III against the Norman king Roger II of Sicily.

In the later part of his reign, John focused his activities on the East, personally leading numerous campaigns against the Turks in Asia Minor. His campaigns fundamentally altered the balance of power in the East, forcing the Turks onto the defensive, while restoring to the Byzantines many towns, fortresses, and cities across the peninsula. He defeated the Danishmend emirate of Melitene and reconquered all of Cilicia, while forcing Raymond of Poitiers, Prince of Antioch, to recognise Byzantine suzerainty. In an effort to demonstrate the Emperor's role as the leader of the Christian world, John marched into the Holy Land at the head of the combined forces of the Empire and the Crusader states; yet despite his great vigour pressing the campaign, his hopes were disappointed by the treachery of his Crusader allies. In 1142, John returned to press his claims to Antioch, but he died in the spring of 1143 following a hunting accident. Raymond was emboldened to invade Cilicia, but he was defeated and forced to go to Constantinople to beg mercy from the new Emperor.

Byzantine Empire in orange, c. 1180, at the end of the Komnenian period

John's chosen heir was his fourth son, Manuel I Komnenos, who campaigned aggressively against his neighbours both in the west and in the east. In Palestine, Manuel allied with the Crusader Kingdom of Jerusalem and sent a large fleet to participate in a combined invasion of Fatimid Egypt. Manuel reinforced his position as overlord of the Crusader states, with his hegemony over Antioch and Jerusalem secured by agreement with Raynald, Prince of Antioch, and Amalric, King of Jerusalem. In an effort to restore Byzantine control over the ports of southern Italy, he sent an expedition to Italy in 1155, but disputes within the coalition led to the eventual failure of the campaign. Despite this military setback, Manuel's armies successfully invaded the Southern parts of Kingdom of Hungary in 1167, defeating the Hungarians at the Battle of Sirmium. By 1168, nearly the whole of the eastern Adriatic coast lay in Manuel's hands. Manuel made several alliances with the Pope and Western Christian kingdoms, and he successfully handled the passage of the Second Crusade through his empire.

In the east, however, Manuel suffered a major defeat in 1176 at the Battle of Myriokephalon, against the Turks. Yet the losses were quickly recovered, and in the following year Manuel's forces inflicted a defeat upon a force of "picked Turks". The Byzantine commander John Vatatzes, who destroyed the Turkish invaders at the Battle of Hyelion and Leimocheir, not only brought troops from the capital but also was able to gather an army along the way, a sign that the Byzantine army remained strong and that the defensive program of western Asia Minor was still successful.