On April 28, 1611, Msgr. Miguel de Benavides together with Father Domingo de Nieva and Father Bernardo de Santa Catalina, founded the Colegio de Nuestra Señora del Santisimo Rosario. It was originally conceived as a school to prepare young men for priesthood. It was later renamed Colegio de Santo Tomas in memory of the foremost Dominican Theologian, Saint Thomas Aquinas. Its original location was within the famous "Walled City" of Manila known as Intramuros.

As a college it already enjoyed the authority to confer academic degrees as early as 1619. The authority became permanent when Pope Innocent X raised it to the status of University of Ecclesiastical and Civil Studies on November 20, 1645, and in 1680, was subsequently placed under Spanish Royal patronage. The Institution has, from the beginning, always been under the governance and administration of the Order of Preachers.

In 1785, King Charles III of Spain bestowed upon the Institution the title Regalia and awarded the Crest of Loyalty or Muy Leal for the exceptional loyalty shown by the administration and students in volunteering to defend Manila against the British invasion. On September 17, 1902, Pope Leo XIII granted it the title Pontificæ (Pontifical) and in 1947, Pope Pius the XII enhanced the new title to The Catholic University of the Philippines.