Educated in Constantinople, Nicholas spent much of his early years in Antioch of Pisidia, where it is believed he took his monastic vows.
He took the emperor's side in the case of Leo of Chalcedon, who protested over Alexios I's confiscation of church treasures to alleviate the financial strain the Byzantine–Norman wars had caused, which was resolved when he presided over the Council of Blachernae in 1094.
He was also prominent in the fight against doctrinal heresy, for instance, Nicholas III condemned as heretical the Bogomil leader Basil the Physician.
In spite of some hostile opposition from the clergy of Hagia Sophia, he ended up supporting Niketas of Ankyra against the emperor's right to elevate metropolitans and exerted a great deal of energy trying to restrict the influence of the Chartophylax.
Meanwhile, the ongoing political situation in the Byzantine Empire especially in Anatolia after the disaster of the Battle of Manzikert forced Nicholas III to seek a union with Pope Urban II, though he was firm in his views about the major contentious issues of the day, principally the Filioque, the azymes, and Papal primacy.