Osaka Prefecture University was incorporated as a public university after reorganization following the integration of former Osaka Prefecture University, Osaka Women's University and Osaka Prefecture College of Nursing. The roots of OPU can be traced back to 1883 with the founding of a training school for veterinary medicine..

Former Osaka Prefecture University was originally established by Osaka Prefectural Government in 1949 as Naniwa University, amalgamating seven technical colleges from Japan's old school system. (Naniwa University changed its name to Osaka Prefecture University in 1955.) The prefectural government had established Osaka Women's University in 1949, replacing its predecessor, also a technical college, and Osaka Prefecture College of Nursing in 1994.

In its previous incarnation, Osaka Prefecture University emphasized the practical sciences, offering courses in the fields of engineering, agriculture, economics, integrated arts and sciences, and social welfare. Osaka Women's University offered a liberal arts program that produced numerous female graduates of high caliber in Women's Studies and other academic disciplines. Both schools garnered international acclaim in research and teaching. Osaka Prefecture College of Nursing developed as an institution that trained expert professionals in high-quality health and medical care to meet sophisticated healthcare needs in Japan's modern age, with a declining birthrate and aging population.

For over five decades, since their founding, these three institutions of higher education have been an important asset to the prefectural administration of Osaka for their ability to produce research results and turn out talented members of society. They have also contributed to the advancement of academic research and higher education in Japan. These three long-established, well-respected prefectural universities were integrated into a single new university in April 2005, operated as a public university corporation.