After that, he was appointed as an assistant of Enrico D'Ovidio at the University of Turin, where he was strongly influenced by Corrado Segre.

He influenced a younger generation of Italian mathematicians and statisticians, including Corrado Gini and Francesco Paolo Cantelli.

In 1922 Benito Mussolini had risen to power and in 1938 a large number of anti-semitic laws were declared, which excluded him, like all other Jews, from public work.

However, during World War II, he organised and taught secret courses for Jewish students — the latter were not allowed to attend university either.

After the liberation of Rome, Castelnuovo was appointed as a special commissioner of the Consiglio Nazionale delle Ricerche in June 1944.

He was given the task of repairing the damage done to Italian scientific institutions by the twenty years of Mussolini's rule.

He became president of the Accademia dei Lincei until his death and was elected a member of the Académie des Sciences in Paris.

He also made a major step in reinterpreting the work on linear series by Alexander von Brill and Max Noether (Brill–Noether theory).

He also wrote a book on calculus, Le origini del calcolo infinitesimale nell'era moderna.