It is one of 66 secondary schools established in provincial capitals and other major cities under the 1836 Plan General de Instrucción Pública.

[3][4] With the discovery of the Americas, the school gained importance in educating young men who would later become a credit to the Spanish Empire.

[4] The school occupies part of the site[6] originally belonging to several former education centers, including the Reales Estudios de San Isidro (1625–1809), formally known as the Colegio Imperial (c. 1590–1625).

[13] The school has educated a wide range of notable figures including four Nobel Prize laureates[4][14] and eight Spanish prime ministers.

[3] Many old pupils went on to fight in the Spanish Civil War, the great majority of them joining the Nationalist side, with around 200 being killed during the two-year conflict.