This study traces the historical process of the emergence of Health Systems Science (HSS) over one hundred years from the 1910s to the 2010s. HSS is a discipline introduced in American medical education as a "third pillar" in addition to basic medical science and clinical medical science. HSS comprises seven core functional domains and four foundational domains, all surrounded by 'system thinking.' According to statistics from 2019 to 2020, 129 universities, or 83.2% of all allopathic and osteopathic medical schools taught HSS before medical clerkship. Additionally, 108 universities, or 69.7% of all medical schools taught HSS during medical clerkship. Although the Progressives in the 1910s sparked discussions about reforming the U.S. national health care system, the National Health Insurance (NHI) debate did not make significant progress from the 1920s through World War II. Efforts to reform the healthcare system gained momentum again in the 1960s. In 1965, a social health insurance program for the elderly called "Medicare" was enacted by revamping the existing social security program. Around the same time, "Medicaid" was also implemented as government-funded health insurance program, distinguishing it from Medicare-a mix of social insurance and government assistance. During the Clinton presidency in the 1990s, political efforts to achieve the NHI by enacting the Health Security Act eventually failed. Almost twenty years later, President Barrack Obama passed the Patient Protection and Affordable Care Act, or ObamaCare, in March 2010. The primary objectives of ObamaCare were to increase the number of insured Americans and reduce health care costs. Post-ObamaCare reforms to the healthcare payment system and changes to the healthcare delivery system have prompted a transformation of the healthcare landscape. The healthcare industry has been pursuing the "triple aim": improving patient experience and population health while reducing costs. To achieve these goals, exposure to a systems-based healthcare environment was necessary. From the 1910s to the 1960s, the model of the ideal physician was the "sovereign physician," who could perform all tasks unilaterally. During this time, doctors were autonomous, independent, and authoritative, and in control of all medical activities. This model was very useful until the mid-twentieth century, when there were many acute illnesses, mainly infectious diseases. Abraham Flexner's 1910 report eventually accelerated the formation of a medical education system based on the two pillars of "basic science-clinical science." During the periods of the 1920s and 1940s, medical education underwent a process of professionalization, standardization, and systematization. World War II did not result in significant changes in medical education. The United States, however, was transforming into a very different society from the prewar period for physicians and Americans. The "New Deal" and World War II led to an expanded role of the federal and state governments in the post-war years. The demand for healthcare was also growing, and the right to healthcare was seen as a fundamental right of all citizens. In the 1960s and 1970s, the current U.S. medical education system was established. Four years of medical school, an internship, and a residency before taking the board examination became the institutional requirements. In the 1980s and 1990s, 'managed care,' represented by Healthcare Maintenance Organizations (HMOs) and Preferred Provider Organizations (PPOs), placed strong controls on both doctors and hospitals (academic healthcare centers). Under the managed care system, academic healthcare centers financially struggled. Moreover, the learning environment on the wards was eroded by shorter patient stays and increased outpatient visits. Since the late 1990s, many medical education organizations, including the Council on Graduate Medical Education (COGME), have called for dramatic reforms to the knowledge and skills of physician education to restore a sustainable U.S. healthcare system. Since 2000, the basic framework of HSS, such as patient safety and value-based healthcare, has been developed. In summary, U.S. healthcare reform efforts since the 1960s-including the expansion of health insurance, managed care and managed competition, and ObamaCare-have led to changes in medical education.