At first founded in 1604 by the king Henri IV, the school was given to the Jesuits in the aim to "instruct the young people and make it fall in love with sciences, honour and virtue, in order to be able to serve".

Françoise d'Alençon, who had become a widow in 1537, decided to retire in her land of La Flèche, which she had received as a gift from her husband Charles de Bourbon.

The "Château-Neuf" (New Castle) was erected between 1539 and 1541 outside of the city, in the place of the Prytanée Militaire and following the plans of the architect Jean Delespine.

With his wife Jeanne d'Albret, inheritor of the Kingdom of Navarre, he stays in La Flèche multiple times, as in February 1552 and then in May 1553, a few months before their son's birth, the future king Henri IV.

On 3 December 1603, by letters patent sent from Rouen, Henri IV authorised the return of the Jesuits, who had been banned by the parliament of Paris in 1594 after the failed attack against the King made by one of their latter pupils, Jean Châtel.

[4] The first Jesuits priests arrive to La Flèche in the beginning of November 1603,[5] led by Pierre Barny, named rector of the college.

[10] Others were Erard Bille, Jacques Buteux, Nicolas Adam, Barthélemy Vimont, Paul Ragueneau, Claude de Quentin, Isaac Jogues.

Three of the five Jesuits sent by Louis XIV to China were from the Collège: Jean de Fontaney, the Superior of the mission, who had been a professor of mathematics there and became rector of the school until 1710 after his return from China; Joachim Bouvet, who was a philosophy student in 1676, became a teacher to the Kangxi Emperor; Claude Visdelou, who was a repetitor and a teacher at the school from 1676 to 1678.

Among others, they educated the future General Bertrand, who accompanied Napoléon to Saint Helena, and the two Chappe brothers, who invented the aerial telegraph.

The school's students are nicknamed "Brutions", as a classic reference to the inhabitants of the Bruttium region of Roman Italy, who had a reputation for their roughness and fighting spirit.