During the interwar period, the school was one of the key Lithuanian institutions in Vilnius Region which was incorporated into the Second Polish Republic and claimed by Lithuania.
[5] The Lithuanian Society for the Relief of War Sufferers hurried to establish a gymnasium which was named after its official founders Jonas Basanavičius, Mykolas Biržiška, and Povilas Gaidelionis [lt].
Lithuania continued to claim Vilnius as its capital leading to a bitter diplomatic conflict with Poland.
Lithuanian organizations remaining in the region faced increased scrutiny and restrictions from the Polish government.
In August 1921, Polish authorities ordered the gymnasium to change its name and move out of the premises on Gediminas Avenue.
[12] In response, the school decided to adopt the name of Grand Duke Vytautas the Great (ruled 1392–1430) but refused to move out.
[3] Many such schools were maintained by the Lithuanian Education Society Rytas and faced increasingly strict requirements by the Polish government.
[18] Additionally, to be allowed to study at the gymnasium, students had to present a certificate that they spoke Lithuanian at home.
With support and funding from the Lithuanian Scientific Society, gymnasium's teachers were active in translating or writing new textbooks.
[11][25] On several occasions, students performed for official delegations visiting from Kraków, Lviv, Silesia to showcase the culture of Vilnius Region.
Students participated in days-long Spiritual Exercises at the Church of Saint Nicholas and processions to Vilnius Calvary.
[26] After Lithuania gained Vilnius in the aftermath of the Soviet–Lithuanian Mutual Assistance Treaty of October 1939, the school was divided into boys' and girls' gymnasiums.
[11] In 1944, after Red Army captured Vilnius in the Operation Bagration, the schools were renamed to the 1st and the 2nd Gymnasiums dropping the historical reference from their names.
At the time, only two other schools in Vilnius were named after people (poet Salomėja Nėris and painter and composer Mikalojus Konstantinas Čiurlionis).
[21] In 2015, a monument to gymnasium's founders Jonas Basanavičius, Mykolas Biržiška, and Povilas Gaidelionis [lt] was built in the schoolyard.