In 1963, The M.S. Hershey Foundation offered $50 million to The Pennsylvania State University to establish a medical school in Hershey. With this grant and $21.3 million from the U.S. Public Health Service, the University built a medical school, research center, and teaching hospital—Penn State Milton S. Hershey Medical Center. The University broke ground in 1966, and Penn State College of Medicine opened its doors to students in 1967. Penn State Hershey Medical Center accepted its first patients in 1970.

The College of Medicine was the first in the nation to have a dedicated Department of Humanities and a Department of Family and Community Medicine. Both were original departments as the College opened.

The original buildings on the Medical Center campus included the Medical Science Building and University Hospital, Animal Research Farm, Laundry and Steam Plant, and University Manor Apartments. Since 1970, the campus has grown from 318 acres to 550 acres. Many additions have been made to the academic and patient care facilities, reflecting the steady increase in patient demand for services and the need to expand research and teaching programs.

Since the first graduate in 1969, Penn State College of Medicine students have become productive physicians and scientists. As of May 2009, the College of Medicine had graduated 3,756 physicians and 938 scientists and other biomedical professionals with Ph.D., M.S., or professional master's degrees.

The College of Medicine offers degree programs in anatomy, biochemistry and molecular biology, bioengineering, cell and molecular biology, genetics, homeland security, immunology and infectious diseases, integrative biosciences, laboratory animal medicine, microbiology and immunology, molecular medicine, molecular toxicology, neuroscience, pharmacology, physiology, and public health sciences. To date, 3,321 resident physicians have been trained in medical specialties at the Medical Center.

Nursing students from Penn State's College of Nursing rotate through the Medical Center for clinical courses, and students from other Penn State health-related programs and other institutions come to Hershey for their clinical experience. The extended B.S. degree program for nurses is offered in conjunction with the College of Nursing.

Continuing education programs serve Medical Center and other health care professionals throughout Pennsylvania, with enrollment exceeding 39,000 each year.

Basic and clinical research to treat and cure major diseases are conducted at the College and Medical Center. Annually this research is supported by more than $100 million in awards from federal, state, and private agencies, businesses, and individuals.

Penn State Hershey Medical Center is recognized as one of the nation's premier academic health centers, recruiting faculty members who are internationally known for their accomplishments in research, education, and patient care. College of Medicine and Medical Center faculty and physicians continue to integrate the latest biomedical knowledge and technology with compassionate care of patients, while educating the next generation of scientists and physicians.