THE DOMINICANS FOUNDED THE COLEGIO de Santo Tomas ― later to become the University of Santo Tomas ― primarily to provide the young Church of the Philippines with locally-trained priests, well-versed in the ecclesiastical sciences. The history of the Central Seminary can, therefore, be traced back to the establishment of the university itself in 1611.

The Colegio originally offered only those courses which were required for preparing men for the priesthood. Consequently, many of its students applied for Holy Orders. In the 18th and 19th centuries, however, additional faculties were opened (Canon Law and Civil Law in 1734, and Medicine and Pharmacy in 1871). In 1894, when the archbishop of Manila requested that clerics be provided with separate living quarters, he was in fact asking the university to open a national or central seminary.

During the annual general conference of bishops in the Philippines held in January 1926, the University of Santo Tomas was chosen to be seat of the Interdiocesan Seminary of the Philippines which was confirmed by the Holy See in 1927. On November 27, 1928, the Sacred Congregation on Universities and Seminaries, by mandate of Pope Pius XI, issued the decree Quod iam provide, for the establishment of the Interdiocesan Seminary of the Philippines.

By the end of 1933, the seminary was transferred from Intramuros to the new campus in Sampaloc, and placed under the direction of its own rector. In 1956, the annex of the seminary was built.

In 2003, the seminary community celebrated its Diamond Jubilee as the Interdiocesan Seminary of the Philippines.