The second State Scientific Secondary School in the city of Padua was established as a separate campus for the "Nievo" school in 1969. During the 1969-1970 school year, the first year the school was in operation, there were 27 classes and 843 pupils and a separate campus in Piove di Sacco with 87 pupils divided into 4 classes.

The building allocated by the Province of Padua to house the new school had long been home to the "Configliachi" Institute for the Blind, an institution that was transferred to a more suitable and better-equipped venue.

The Teaching Board approved the students' and professors' explicit request to name the school after "Enrico Fermi" on December 12the of that same year. Enrico Fermi was a man and a scientist whose deep influence can be traced in the events in Italy during the twentieth century. The Secondary School chose to adopt him as a reference figure for his energy and balance, as well as for the simple and sincere way he lived his life.

In recent years, the school has become well-known thanks to its position as the leading school in Padua in reference to the university results of its past students (2015), also ranking among the best schools in Italy. Furthermore, the school candidates itself for many projects in both the humanities and sciences: for example, learning experiences featuring highly technological and scientific content such as participation in "Zero Robotics" and the "Baby Goldrake" inter-institutional cooperation program. In national and international competitions such as the Italian Olympics, Mathematical and Physics Games, the school has continuously recorded prestigious results over the years.