Background: Hand, foot, and mouth disease (HFMD) is a common infectious disease among children. Guangdong Province is one of the most severely affected provinces in south China. This study aims to identify the spatiotemporal distribution characteristics and potential predictors of HFMD in Guangdong Province and provide a theoretical basis for the disease control and prevention. Methods: Case-based HFMD surveillance data from 2009 to 2012 was obtained from the China Center for Disease Control and Prevention (China CDC). The Bayesian spatiotemporal model was used to evaluate the spatiotemporal variations of HFMD and identify the potential association with meteorological and socioeconomic factors. Results: Spatially, areas with higher relative risk (RR) of HFMD tended to be clustered around the Pearl River Delta region (the mid-east of the province). Temporally, we observed that the risk of HFMD peaked from April to July and October to December each year and detected an upward trend between 2009 and 2012. There was positive nonlinear enhancement between spatial and temporal effects, and the distribution of relative risk in space was not fixed, which had an irregular fluctuating trend in each month. The risk of HFMD was significantly associated with monthly average relative humidity (RR: 1.015, 95% CI: 1.006–1.024), monthly average temperature (RR: 1.045, 95% CI: 1.021–1.069), and monthly average rainfall (RR: 1.004, 95% CI: 1.001–1.008), but not significantly associated with average GDP. Conclusions: The risk of HFMD in Guangdong showed significant spatiotemporal heterogeneity. There was spatiotemporal interaction in the relative risk of HFMD. Adding a spatiotemporal interaction term could well explain the change of spatial effect with time, thus increasing the goodness of fit of the model. Meteorological factors, such as monthly average relative humidity, monthly average temperature, and monthly average rainfall, might be the driving factors of HFMD.