The Willamette University School of Medicine, OHSU's earliest predecessor, was founded in the 1860s in Salem, and was relocated to Portland in the 1870s.

"Sam" Jackson, publisher of the now-defunct Oregon Journal donated the remaining 88 acres (36 ha) to the school two years prior to the move after the property had been deemed unsuitable for the construction of a railroad yard.

[12] Over the next forty years, the school diversified its educational offerings to include nursing and dental programs,[13] and expanded with facilities built during this time on Marquam Hill, including the Multnomah County Hospital, the Doernbecher Children's Hospital, and an outpatient clinic.

The merger was funded in part by a $4 million grant from the M.J. Murdock Charitable Trust, earmarked to help launch a new biomedical engineering program at the School.

The procedure is intended to reverse a genetic mutation causing Leber congenital amaurosis, a form of inherited blindness.

[23] The United States Department of Agriculture cited OHSU in February 2020 for animal welfare violation after five prairie voles in its lab died of thirst.

The university was also cited for practices that risked contaminating surgical tools during procedures for probing a ferret's brain with an electrode.

The university maintains a number of outpatient primary care facilities including the Physician's Pavilion at the Marquam Hill campus as well as throughout the Portland metropolitan area.A third hospital, the Portland Veterans Affairs Medical Center[26] is located next to the main OHSU campus; this hospital is run by the United States Department of Veterans Affairs and is outside the auspices of OHSU.

[28] This campus specialized in graduate-level science and engineering education and is located in the heart of Oregon's Silicon Forest.

Since 1998, the university has controlled the Oregon National Primate Research Center, located adjacent to OGI in Hillsboro.With the Marquam Hill campus running out of room for expansion, beginning in 2003 OHSU announced plans to expand into the South Waterfront District, formerly known as the North Macadam District.

As part of the continued expansion of the South Waterfront, on June 26, 2014, OHSU opened the Collaborative Life Sciences Building (CLSB).

OHSU will work out of the adjacent Torrey Pines Institute for Molecular Studies until its own center is completed.

The graduate nursing program was most recently ranked 7th overall in the nation by the U.S. News & World Report and 5th in the gerontology/geriatric specialty.

[43] The Oregon Health & Science University Foundation[44] is a 501(c)(3) organization that exists to advance OHSU's mission through philanthropy.

After the purchase, OHSU began developing plans with the Portland Office of Transportation to connect this location to its Marquam Hill facilities by way of an aerial tram.

[48] The research, which was being conducted in conjunction with Oregon State University was designed to understand the biological mechanisms involved in sexual partner preference.