He was born in Constantinople around 758, of pious parents: his father had been exiled under Constantine Copronymus for his steadfast veneration of the holy icons. Nikephoros served in the imperial palace as a secretary, but later renounced worldly success to struggle in monastic life near Constantinople. He built and administered a monastery which soon became filled with monks; but he himself never took the monastic habit, feeling himself unworthy. Though a layman, he took part in the Seventh Ecumenical Council at the request of the Emperor and Patriarch because of his remarkable knowledge of Holy Scripture. Much against his will, he was made Patriarch of Constantinople at the death of Patriarch Tarasios. He was made a monk, then elevated through all the priestly orders in a few days, then enthroned at St Sophia in 806.

A few years later, the Emperor Leo the Armenian took the throne. Patriarch Nikephoros, as was customary, sent him a Confession of the Orthodox Faith to sign. Leo put off signing the document until his coronation, then revealed himself to be an Iconoclast heretic. The Patriarch tried quietly to bring him back to the Orthodox faith, but to no avail. When the Emperor, in his turn, tried to make the holy Nikephoros bow to iconoclasm, the Patriarch clearly and publicly upheld the veneration of the holy Icons. For this he was deposed and driven into exile at the Monastery of St Theodore, which he himself had founded. Here he reposed, having served for nine years as Patriarch, and thirteen years in exile and privation.