The College of Arts and Sciences started as the University Extension Division in June 21, 1951. Its location was the University's 1908 Manila campus – the original cradle of UP. Its mission was to offer evening classes for working students.
In the beginning, the only courses offered were programs leading to an Associate in Arts or a Bachelor's degree in Arts, Business Administration, Education and Law. There were three graduate programs namely Master of Arts, Master of Education, and the Master in Industrial Management.
In 1970, the Manila unit was elevated to college status with its new name of UP Extension in Manila. The designation of its head was changed from director to dean. Prof. David Wico, who was director from 1958 to 1969 became UP Extension Manila's first dean.
From 1973 - 1978, the College instituted day classes at Rizal Hall. The college underwent an expansion of its core faculty members and administrative personnel. The expansion also led to the creation of three academic committees which later evolved into the Division of Humanities, Division of Physical and Biological Sciences, and the Division of Social Sciences. The BS Biological Sciences program was also instituted.
In response to UP President O.D. Corpuz's Executive Order No. 17, the College emphasized its mission of providing the liberal arts and basic science education in UP Manila. AB Development Studies, was also offered.
When Atty. Edgardo J. Angara became the UP president, he created the Committee to Review Academic Programs (CRAP) which re-examined curricular offerings, and the Management Review Committee (MRC) which re-examined the organizational structure and management of the University.
The Board of Regent's approval of a recommendation by MRC made possible the creation of the autonomous University of the Philippines Manila on March 23, 1983, with the College of Arts and Sciences providing the general education curriculum for the health sciences programs.
The Division of Physical and Biological Sciences was renamed the Division of Natural Sciences and Mathematics and the BS Biological Sciences became BS Biology. New curricular offerings which included the BA Organizational Communication and BA Philippine Arts were instituted between 1984-1987.
The divisions were increased to five and renamed departments in the period 1987-1994. The Departments were Biology, Arts and Communication (formerly the Division of Humanities), Physical Education, Physical Sciences and Mathematics (formerly the Division of Natural Sciences and Mathematics), and Social Sciences. As the CAS expanded its vision, the Department of Behavioral Sciences was created in 2002 as the sixth department.
The BS Biochemistry program and the BS Computer Science were instituted in 1996. Effective FS 2011-2012 the BS Applied Physics was also offered by the DPSM. The Master of Management (Public Management and Business Management) was implemented in 1999.
In line with UP's thrust for a revitalized GE Program, the CAS became the forerunner in the General Education Program, revitalizing existing courses and proposing new ones that aligned with the UP Manila's role as the Health Sciences Center of the UP System.
The MS Health Informatics, a joint program with the College of Medicine was approved and implemented in 2005.