This study explores the interdisciplinary dynamics and characteristics of major original scientific achievements. Based on the perspective of knowledge integration, it combines bibliometric and social network analysis to investigate key publications of Nobel-winning research in natural science and their reference data. The data cover 585 laureates in Chemistry, Physics, and Physiology or Medicine awarded between 1901 and 2020, as well as 835 key publications published between 1887 and 2012 and their 10,894 citation publications. The main findings are as follows: First, interdisciplinary knowledge integration is an essential feature of original scientific breakthroughs, although influential achievements typically result from a novel combination of a larger amount of distant knowledge but in fewer disciplines. Second, the development of various disciplines in natural science has followed different dynamics of interdisciplinary processes for more than 100 years. Chemistry and Physics have experienced a dynamic shift from centralization to decentralization in terms of the concentrated degree of integrated disciplines, while Physiology or Medicine has shown a more generally concentrated trend. Third, Nobel-winning research presents a trend of a greater degree of knowledge interconnection, and the migration of combined research methods, tools, and basic disciplines contributes to the increasingly intense structure of knowledge combination. Bridging disciplines that facilitate knowledge exchange have shifted in the knowledge network across three time periods (the 1900s–1940s, 1950s–1970s, and 1980s and beyond).