Nicephorus, who belonged to the military aristocracy of Asia Minor and who was related to the powerful Phocas family, became commander of the Anatolian theme (administrative district). When discontent against the government of Michael VII Ducas led to rioting in Constantinople, Nicephorus was proclaimed emperor (January 7, 1078) by his supporters there. With some support from Suleiman, the Seljuq ruler in Anatolia, Nicephorus was acclaimed emperor by his troops at Nicaea (in northwestern Anatolia) and entered Constantinople three months later. His imperial claim was ratified by the aristocracy and clergy, who had already deposed Michael VII. Nicephorus III defeated a rival claimant to the throne, Nicephorus Bryennius (Bryennius, Nicephorus), the empire's commander in Albania; he also defeated a later pretender, Nicephorus Basilacius, who succeeded Bryennius in Albania.

After the death of Nicephorus's wife, he married Mary, the wife of the deposed but still living Michael VII, naming Michael's son Constantine as his successor but then later deciding on one of his own nephews instead. He relegated Constantine's fiancée, a daughter of the Norman leader Robert Guiscard, to a convent. Nicephorus's action provided an excuse for Guiscard's later successful attacks against the empire.

In 1080 another usurper, Nicephorus Melissenus, appeared in Asia Minor (Anatolia) and also sought Turkish assistance. As a result of such constant internal strife, with one faction or another requesting aid from the Turks, most of Asia Minor was lost to Byzantium and became incorporated in the Seljuq sultanate of Rūm, centred on Iconium (modern Konya, Turkey). A rebellion led by Alexius I Comnenus successfully captured Constantinople, forcing Nicephorus to abdicate on April 4, 1081. He entered the Peribleptos Monastery in Constantinople, which he had restored.