He started studying mathematics in 1901 at Moscow University, where his advisor was Dimitri Egorov. Luzin went through a personal crisis in the years 1905 and 1906. He wrote to Pavel Florensky that: You found me a mere child at the University, knowing nothing. I don't know how it happened, but I cannot be satisfied any more with analytic functions and Taylor series ... it happened about a year ago. ... To see the misery of people, to see the torment of life, to wend my way home from a mathematical meeting ... where, shivering in the cold, some women stand waiting in vain for dinner purchased with horror - this is an unbearable sight. It is unbearable, having seen this, to calmly study (in fact to enjoy) science. After that I could not study only mathematics, and I wanted to transfer to the medical school. ... I have been here about five months, but have only recently begun to study. From 1910 to 1914 he studied at Göttingen, where he was influenced by Edmund Landau. He then returned to Moscow and received his Ph.D. degree in 1915. During the Russian Civil War (1918 – 1920) Luzin left Moscow for the Polytechnic Institute Ivanovo-Voznesensk (now called Ivanovo State University of Chemistry and Technology). He returned to Moscow in 1920. On 5 January 1927 Luzin was elected as a corresponding member of the USSR Academy of Sciences and became a full member of the USSR Academy of Sciences first at the Department of Philosophy and then at the Department of Pure Mathematics (12 January 1929).

In the 1920s Luzin organized a famous research seminar at Moscow University. His doctoral students included some of the most famous Soviet mathematicians: Pavel Aleksandrov, Nina Bari, Aleksandr Khinchin, Andrey Kolmogorov, Alexander Kronrod, Mikhail Lavrentyev, Alexey Lyapunov, Lazar Lyusternik, Pyotr Novikov, Lev Schnirelmann and Pavel Urysohn.

The first significant result of Nikolay Luzin was a construction of an almost everywhere divergent trigonometric series with monotonically converging to zero coefficients (1912). This example disproved the Pierre Fatou conjecture and was unexpected to most mathematicians at that time. His Ph.D. thesis entitled "Integral and trigonometric series" (1915) made a large impact on the subsequent development of the metric theory of functions. A set of problems formulated in this thesis for a long time attracted attention from mathematicians. For example, the first problem in the list, on the convergence of the Fourier series for a square-integrable function, was solved by Lennart Carleson in 1966. In the theory of boundary properties of analytic functions he proved an important result on the invariance of sets of boundary points under conformal mappings (1919). Luzin was one of the founders of descriptive set theory. He also made contributions to complex analysis, theory of differential equations, numerical methods.

On 21 November 1930 the declaration of the “initiative group” of the Moscow Mathematical Society which consisted of former Luzin's students Lazar Lyusternik and Lev Shnirelman along with Alexander Gelfond and Lev Pontryagin claimed that “there appeared active counter revolutionaries among mathematicians.” Some of these mathematicians were pointed out, including the advisor of Luzin, Dmitri Egorov. In September 1930, Dmitri Egorov was arrested on the basis of his religious beliefs. After arrest, he left the position of the director of the Moscow Mathematical Society. The new director became Ernst Kolman. As a result, Luzin left the Moscow Mathematical Society and Moscow State University. Egorov died on 10 September 1931, after a hunger strike initiated in prison. In 1931, Ernst Kolman made the first complaint against Luzin. In July-August 1936, Luzin was criticised in Pravda in a series of anonymous articles whose authorship later was attributed to Ernst Kolman. It was alleged that Luzin published “would-be scientific papers,” “felt no shame in declaring the discoveries of his students to be his own achievements,” stood close to the ideology of the “black hundreds,” orthodoxy, and monarchy “fascist-type modernized but slightly.” Luzin was tried at a special hearing of the Commission of the Academy of Sciences of the USSR, which endorsed all accusations of Luzin as an enemy under the mask of a Soviet citizen. One of the complaints was that he published his major results in foreign journals. This method of political insinuations and slander was used against the old Muscovite professorship many years before the article in Pravda.

The political offensive against Luzin was launched not only by Stalin's repressive ideological authorities, but also by a group of Luzin's students headed by Pavel Alexandrov. Although the Commission convicted Luzin, he was neither expelled from the Academy nor arrested. There has been some speculation about why his punishment was so much milder than that of most other people condemned at that time, but the reason for this does not seem to be known for certain. Historian of mathematics A.P. Yushkevich speculated that at the time, Stalin was more concerned with forthcoming Moscow Trials of Kamenev, Zinoviev and others, and that the eventual fate of Luzin was of little interest to him. Still, Luzin was never rehabilitated even after Stalin's death.