The Healthy China initiative is one of the important strategies in the new period of China. Hand, foot, and mouth disease (HFMD) is a global health threaten. It is a typical infectious disease with a wide and universal impact in China, especially to infants. This paper develops a theoretical framework for the study of infectious diseases from the health geography perspective. The framework used concentration and spatial analysis methods to analyze the spatio-temporal differentiation and evolution patterns of HFMD incidence in China from 2008 to 2017. Using spatial correlation analysis and geographic detection of 18 risk factors for the incidence of HFMD, we identified the main influencing factors and revealed the mechanism of the geographic distribution of HFMD. The results show that: (1) the theoretical framework of infectious disease research from the perspective of health geography includes three subsystems: the basic link of infectious disease, influencing factors, and the distribution and diffusion state of the infectious disease with mutual interaction and impact between and within the three subsystems. (2) From 2008 to 2017, the incidence rate of HFMD in China showed a fluctuating increase, with a two-year cycle. In addition, the incidence in the even years was higher than that in the odd years. The peaks of incidence are observed in late spring, early summer, late autumn, and early winter. (3) The incidence rate of HFMD from 2008 to 2010 did not reflect obvious characteristics of the spatial agglomeration. However, the incidence rate had a strong spatial autocorrelation from 2011 to 2017. Hotspots were mainly distributed in southern humid areas such as Guangdong, Guangxi, and Hainan. Moreover, the spots were evolving from north to south, and changing from small and scattered to large and concentrated spots. HFMD mainly occurred in three typical areas, namely, areas with hot and humid climates, economically underdeveloped areas with poor medical resources, and densely populated areas prone to clustered infections. (4) Twelve factors have passed the test of significance of correlation analysis and geographical detection. The explanatory power of the factors that positively affect the incidence rate are sorted as follows: AT > AP > RH > BP > PD > RND > PCG; factors that have negative correlation are sorted as follows: SD > WS > AQI > DEM > HBP. The interaction between AT and AP and other factors is the most obvious. This study provides an empirical basis for research into HFMD's health geography, pathology, and epidemiology, and important scientific support and policy reference for serving the strategy of Healthy China and epidemic control and prevention.