[2] The seed of Christianity was planted first in the town of Majayjay in 1571, as Augustinian missionaries were in the place and made contact with the natives.

The Philippine Independent Church, known popularly as Aglipayans, took hold of their presence in some towns such as Santa Cruz and Nagcarlan.

In 1917, a seminario menor was opened under the auspices of the priests of the Congregation of the Mission until 1941 in San Pablo City.

The new diocese was erected through the Apostolic Constitution Ecclesiarum per ampla[3] on November 28, 1966, by Pope Paul VI.

Following San Diego's appointment as Bishop of Pasig, he was succeeded by Leo M. Drona, a Salesian, in 2004 until his retirement in 2013.

The diocese was then led by Buenaventura M. Famadico, who was installed as fourth Bishop of San Pablo on March 2, 2013.

During his evangelization work in the Philippines, St. Pedro Bautista was tasked to teach music and plainchant to the natives in Santa Ana, Manila.

With Pedro Bantigue as the newly appointed bishop at that time, he established a seminary, following the canonical erection of the Diocese of San Pablo.

It is currently located in Barangay Concepcion, San Pablo city and serves as the philosophy college seminary of the diocese.