The opening ceremony of the new Peking Union Medical College held on September 15 to 22, 1921, has an epoch-making, milestone, international, and diversified historical significance in China and the world. It not only marks the beginning of modern Western medicine education and Western medicine clinical diagnosis and treatment services in China, but also marks the first year of the construction of China’s modern hospital and medical, health and mental health social work practice system, kicking off the 100-year history of the construction of China’s social work practice system of modern health and mental health. From the perspective of institutional social history and historical institutionalism, this paper, for the first time, divides the century-old history from 1921 to 2021 into four periods by means of literature review, history-comparative study, content analysis and theoretical construction. With the introduction of Western medicine, the period from 1840 to 1920 was mainly for medical charity, medical assistance and health public welfare. From 1921 to 1949, the foundation and rapid development of the modern hospital and medical, health and mental health social work practice system were established. From 1950 to 1977, sociology and professional social work practice stopped and disappeared. From 1978 to 2021, China’s modern hospitals and medical, health and mental health social work practice system was restored, restructured, structurally transformed, and fully developed, and the social work profession return to specialized, theoretical, policy-based, localized, and institutionalized. Each historical period has several distinctive and prominent characteristics of the times. The purpose is to clearly depict the overall picture of the century-old historical changes in the construction of China’s social work practice system of modern health and mental health. More importantly, for the first time, this article analyzes the influencing factors and social causes of the development of China’s health and mental health social work practice system, and comprehensively, systematically, historically and objectively summarizes the century-old historical experience, lessons and laws of China’s health and mental health social work practice system. This study aims to provide a professional social work practice system, wisdom and law of modern social welfare system for the realization of the second Centenary Goal, healthy China, the rule of law in China and welfare China system construction, to meet the needs of the whole people and universal benefits of a better life.