Abstract: The hand, foot, and mouth disease (HFMD) epidemic has become a serious public health problem worldwide with a high economic and health burden. In addition, the prevalence of HFMD varies greatly between cities. Therefore, this paper aims to reveal high-risk cities for HFMD and associated meteorological and air pollution factors in Guangdong Province during 2014-2018. Data on the incidence of HFMD and meteorological and air pollution factors were obtained from the Guangdong Provincial Center for Disease Control and Prevention and Guangdong Meteorological Service. Three different grey incidence analysis (GIA) were used, namely Deng’s grey incidence analysis, absolute degree of GIA, and second synthetic degree of GIA. Additionally, GM(1,1) model was used to predict the trend of HFMD in 2019-2028. According to the second synthetic degree of GIA, the top three cities most affected by HFMD are Zhuhai, Guangzhou, and Foshan. However, the prediction model found that the incidence of HFMD in Guangdong Province will generally decline in the next 10 years, indicating that the prevention and control measures are still relatively in place. Deng’s grey incidence analysis found that CO, SO2, PM2.5, PM10, and wind scale are closely related to the incidence of HFMD. It is recommended to closely monitor weather change and urban air quality and take protective measures against HFMD in advance. The results of this study have substantial implications for the control of HFMD.