Although three monovalent EV-A71 vaccines have been launched in mainland China since 2016, hand, foot, and mouth disease (HFMD) still causes a considerable disease burden in China. Vaccines' use may change the epidemiological characters of HFMD. Spatial autocorrelation analysis and space-time scan statistics analysis were used to explore the spatiotemporal distribution pattern of this disease at the provincial level in mainland China. The effects of meteorological factors, socio-economic factors, and health resources on HFMD incidence were analyzed using Geodetector. Interrupted time series (ITS) was used to analyze the impact of the EV-A71 vaccine on the incidence of HFMD. This study found that the median annual incidence of HFMD was 153.78 per 100,000 (ranging from 120.79 to 205.06) in mainland China from 2011 to 2018. Two peaks of infections were observed per year. Children 5 years and under were the main morbid population. The spatial distribution of HFMD was presented a significant clustering pattern in each year (P<0.001). The distribution of HFMD cases was clustered in time and space. The range of cluster time was between April and October. The most likely cluster appeared in the southern coastal provinces (Guangxi, Guangdong, Hainan) from 2011 to 2017 and in the eastern coastal provinces (Shanghai, Jiangsu, Zhejiang) in 2018. The spatial heterogeneity of HFMD incidence could be attributed to meteorological factors, socioeconomic factors, and health resource. After introducing the EV-A71 vaccine, the instantaneous level of HFMD incidence decreased at the national level, and HFMD incidence trended downward in the southern coastal provinces and increased in the eastern coastal provinces. The prevention and control policies of HFMD should be adapted to local conditions in different provinces. It is necessary to advance the EV-A71 vaccination plan, expand the vaccine coverage and develop multivalent HFMD vaccines as soon as possible.