Son of John of Luxembourg he was born towards the end of 1321. With great tenacity his brother Charles IV, king of Bohemia, worked to take over from Bertrand de Saint-Geniès, murdered dead, as Patriarch of Aquileia. The political importance of Friuli and its Alpine passes in view of the imperial coronation in Rome prompted Charles IV to choose a relative for the position of lord of Friuli.
Pope Clement VI consented to the insistence of the king and on October 22, 1350 appointed Nicolò patriarch of Aquileia. One of the first political moves by Nicolò consisted in the prosecution and punishment of the killing of Patriarch Bertrando.
The punitive action was undertaken with brutality: until the spring of 1351 numerous castles were destroyed and many of the conspirators were condemned, even by beheading. He followed the expectations of the citizens of Cividale, begging his brother Carlo to grant the city the privilege of foundation of the University.
The king allowed the start of a "Studium" of liberal arts and law, but above all granted to the new University the faculty to assign doctoral degrees (Prague, 1 August 1353). Despite all these efforts, no academic activity took place in Cividale, which was never a destination for students. Nicolò personally welcomed his brother Carlo IV to Udine, who traveled to Rome via Friuli and accompanied his brother on the journey that led him to the coronation, holding several months in Siena and Pisa as captain and as "vicarius generalis" of Tuscany. In Pisa he was the victim of an uprising against his person and was, therefore, taken prisoner, while in the meantime in Friuli too, actions of revolt against his authority took place.
In the cities of Udine and Cividale, the captains he installed were killed. On his return to Friuli and until his death, his political activity should be seen as a reaction to the difficulties arising at the hands of internal and external enemies rather than as the implementation of specific projects or strategies.
He died on 29 July 1358 in Belluno where he received a first burial: only later his remains were transferred to the cathedral of Udine.