The College of Science was established in 1926 as the College of Liberal Arts. It initially offered four-year programs for Bachelor of Arts and Bachelor of Science degrees and two-year courses in Preparatory Law and Preparatory Medicine. Through the succeeding years, it expanded its offerings in response to the needs of national development and introduced innovative degree programs including Bachelor of Science in Chemistry (1931), Bachelor of Science in Industrial Technology (1941), Bachelor of Science major in Zoology (1947), Bachelor of Science major in Psychology (1948), and Bachelor of Science major in Mathematics and Physics (1952).

In 1964, the College of Liberal Arts was transformed into the College of Science, after ceding the Bachelor of Arts program to the Faculty of Arts and Letters. Thereafter, all programs offered by the College focused only on science and mathematics. Ever sensitive to the demands of national growth, the college initiated new programs including B.S. (General) (1964), B.S. Mathematics (1966), B.S. Actuarial Sciences (1974), B.S. Biology (1978), B.S. Microbiology (1979), B.S. Computer Science (1984), B.S. Information Technology and B.S. Information Management (1999), and B.S. Applied Physics (2002). In 2003, the Computer Science, Information technology and Information Management programs were transferred to the Faculty of Engineering. In the year 2009, a shift from theoretical to applied mathematics was implemented with the realignment of B.S Mathematics Major in Actuarial Science to B.S Applied Mathematics Major in Actuarial Science.

Excellence in science education and research has been a byword of the UST-College of Science. In September 2011, the college has been awarded by the Philippine Association of the Colleges and Universities Commission on Accreditation (PACUCOA) the highest accreditation of Level IV, the first in the University of Santo Tomas. Having been accredited Level IV, the college became instrumental in the Institutional Accreditation Status of the university awarded by the Federation of Accrediting Agencies of the Philippines (FAAP) in September 2012. In recent years, the Commission on Higher Education (CHED) has recognized the Department of Biological Sciences as a Center of Excellence in Biology and Microbiology; the Department of Chemistry as a Center of Excellence in Chemistry; and, the Department of Psychology as a Center of Excellence in Psychology.