During the early years of the College of Arts and Sciences, the Department of Physical and Biological Sciences (DPBS) provided services for physical education, biology, mathematics, and natural sciences subjects.

In 1985, the DPBS was split into two units: the Department of Physical Education (DPE) and the Division of Natural Sciences and Mathematics (DNSM).

In response to the need for the development of separate disciplines of biology and the physical sciences, the DNSM was reconstructed into the Department of Biology (DB) and the Department of Physical Sciences and Mathematics (DPSM).

Approved by the Board of Regents (BOR) in 29 August 1991, the restructuring was done to provide a systematic and orderly utilization of the necessary manpower and facilities in the teaching of the programs. The department currently serves the needs for biochemistry, chemistry, computer science, health informatics, bioinformatics, geology, mathematics and physics subjects of the different U.P. Manila colleges.

In 1996, DPSM launched two programs: B.S. Biochemistry and B.S. Computer Science.

In 2003, the B.S. Computer Science started to offer two tracks of specialization: Health Informatics and Statistical Computing.

In 2005, the Department in collaboration with the Medical Informatics Unit (MIU) of the College of Medicine started offering the graduate program M.S. Health Informatics with two tracks of specialization: Bioinformatics (which is handled by DPSM)  and Medical Informatics (which is handled by MIU).

In 2011, the Department offered its third undergraduate program, B.S. Applied Physics (Health Physics).