The story of Seminario Mayor de San Carlos traces its roaots to the Colegio de San Ildefonso, founded by the Society of Jesus on August 21, 1595. This mission school aimed to educate native boys in the basics of the newly-planted Christian faith. However, its closure in 1769, following the expulsion of the Jesuits by King Carlos III of Spain, marked the end of its first chapter.

On October 25, 1777, Bishop Mateo Joaquin Rubio de Arevalo petitioned the King to repurpose the Colegio for priestly training in the Diocese of Cebu. With a royal decree granted in 1779, the Real Seminario de San Carlos formally opened in 1825. Named in honor of San Carlos Borromeo, the patron saint of priestly formation, the seminary was entrusted to the Diocesan Clergy of Cebu.

The seminary flourished under the guidance of Dominican Regents of Studies and, later, the Padres Paules of the Congregation of the Missions. Inspired by the spirit of San Vicente de Paul, they formed "learned and zealous pastors of souls," ready to serve even in the most remote areas.

In 1867, the seminary expanded to admit extern students, becoming the Colegio-Seminario de San Carlos. Among its notable alumni were Juan Bautista Gorordo, the first Filipino Bishop of Cebu, and Sergio Osmeña, President of the Philippine Commonwealth.

The Revolution for Independence in 1898 and the Japanese occupation during World War II forced the seminary to close multiple times. Yet, it persisted. Classes resumed in temporary locations, and by 1949, the seminary moved to a new building in Mabolo, thanks to the leadership of Archbishop Gabriel Reyes.

To accommodate growing vocations, Archbishop Julio Rosales established separate facilities for high school, college, and theology seminarians. By 1973, the seminary came to be known as Seminario Mayor de San Carlos.

The Vincentians continued their mission until 1998, when administration was officially transferred to the Diocesan Clergy of Cebu under His Eminence Ricardo J. Cardinal Vidal. The seminary embraced reforms from the Second Vatican Council, introduced a Pastoral Formation Year in 1985, and expanded its programs to include graduate studies in Theology and Pastoral Ministry by 1996.

Today, Seminario Mayor de San Carlos stands as a beacon of faith and formation, shaping future priests and lay leaders to serve with zeal and humility, continuing a legacy over four centuries strong.