USC was formerly known as the Colegio de San Ildefonso which founded by the Spanish Jesuits on August 1, 1595. In 1769, it was closed upon the expulsion of the Jesuits from the Philippines. It reopened in 1783 along Martires Street on the initiative of Bishop Mateo Joaquin de Arevalo under the name Colegio-Seminario de San Carlos, named after St. Charles Borromeo, the great patron of ecclesiastical training in the Renaissance. In 1867, the Vincentians took over the administration of San Carlos.

There was a rapid expansion of the University during the 60s under the leadership of foreign priest-academicians came with the decade’s wave of militant nationalism, which culminated in calls for the Filipinization of the administration of all Catholic schools in the country. USC continued to experience growth in the following decades. Recently, the school regularly produces topnotchers in board exams and alumni who have earned public recognition for achieving excellence in their own fields. This is proof that USC has remained true to its commitment to excellence in education.