Hand, foot, and mouth disease (HFMD) is a highly contagious viral illness. Understanding the long-term trends of HFMD incidence and its epidemic characteristics under the circumstances of the enterovirus 71 (EV71) vaccination program and the outbreak of COVID-19 is crucial for effective disease surveillance and control.We aim to give an overview of the trends of HFMD over the past decades and evaluate the impact of the EV71 vaccination program and the COVID-19 pandemic on the epidemic trends of HFMD.Using official surveillance data from the Yunnan Province, China, we described long-term incidence trends and severity rates of HFMD as well as the variation of enterovirus proportions among cases. We conducted the autoregressive integrated moving average (ARIMA) of time series analyses to predict monthly incidences based on given subsets. The difference between the actual incidences and their counterfactual predictions was compared using absolute percentage errors (APEs) for periods after the EV71 vaccination program and the COVID-19 pandemic, respectively.The annual incidence of HFMD fluctuated between 25.62 cases per 100,000 people in 2008 and 221.52 cases per 100,000 people in 2018. The incidence for men ranged from 30 to 250 cases per 100,000 people from 2008 to 2021, which was constantly higher than that for women. The annual incidence for children aged 1 to 2 years old ranged from 54.54 to 630.06 cases per 100,000 people, which was persistently higher than that for other age groups. For monthly incidences, semiannual peaks were observed for each year. All actual monthly incidences of 2014 to 2015 fell within the predicted 95% CI by the ARIMA(1,0,1)(1,1,0)[12] model. The average APE was 19% for a 2-year prediction. After the EV71 vaccination program, the actual monthly incidence of HFMD was consistently lower than the counterfactual predictions by ARIMA(1,0,1)(1,1,0)[12], with negative APEs ranging from -11% to -229% from January 2017 to April 2018. In the meantime, the proportion of EV71 among the enteroviruses causing HFMD decreased significantly, and the proportion was highly correlated (r=0.73, P=.004) with the severity rate. After the onset of the COVID-19 pandemic in 2020, the actual monthly incidence of HFMD consistently maintained a lower magnitude compared to the counterfactual predictions-ARIMA(1,0,1)(0,1,0)[12]-from February to September 2020, with considerable negative APEs (ranging from -31% to -2248%).EV71 vaccination alleviated severe HFMD cases and altered epidemiological trends. The HFMD may also benefit from nonpharmaceutical interventions during outbreaks such as the COVID-19 pandemic. Further development of a multivalent virus vaccine is crucial for effectively controlling HFMD outbreaks. Policymakers should implement nonpharmaceutical interventions and emphasize personal hygiene for routine prevention when appropriate.© Jia Nie, Tian Huang, Yuhong Sun, Zutong Peng, Wenlong Dong, Jiancheng Chen, Di Zheng, Fuyin Guo, Wenhui Shi, Yuewei Ling, Weijia Zhao, Haijun Yang, Tiejun Shui, Xiangyu Yan. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org).