The son of Count John I Orsini and Maria, an Epirote princess, he succeeded his father upon the latter's death, and in the next year murdered his uncle, Thomas Komnenos Doukas, and usurped his rule of Epirus.

Nicholas' attempts to ally with the Republic of Venice and recover Ioannina failed, and he was in turn killed by his brother John II Orsini in 1323.

[3][7] In 1318 he surprised and murdered his childless uncle, Thomas I Komnenos Doukas of Epirus,[8][9] and easily subdued the entire southern portion of the principality around Arta.

[3][10] While Nicholas had sworn allegiance to the new Prince of Achaea, John of Gravina in 1318 as the latter's feudal vassal,[11] in the next year, when prompted to render homage as ruler of Epirus as well, he refused.

In May 1320 he sent ambassadors to Venice, offering to acknowledge Venetian overlordship and hand over either the lucrative fishing grounds of Lake Butrint, or the sugarcane plantations of Parga.