OBJECTIVE: This study analyzed the influence of urbanization on the effectiveness of school closures in controlling hand, foot, and mouth disease (HFMD). METHODS: Data were collected from 31 provinces in mainland China between 2010 and 2019. The effect of school closures on HFMD was estimated and synthesized for high and low urbanization groups. Discrepancies in effectiveness were hypothesized to be explained by transmission potential, which was estimated with its influencing factors identified. Considering time lags or seasons, system dynamics models were constructed to verify this hypothesis. RESULTS: The relative risk of school closures on HFMD epidemics was 0.68, with a negative correlation between urbanization and the effectiveness of school closures. Urbanization and human mobility significantly increased the transmission potential of HFMD. Controlling for the positive effects of specific humidity, school closures reduced the effective reproductive number of HFMD by 10.52% and 17.07% in the high and low urbanization groups, respectively (P <
0.0001). Timely response or school closures in autumn led to a notable decline in the number of HFMD cases. CONCLUSIONS: Increased urbanization reduced the effectiveness of school closures in controlling HFMD by greater transmission potential, highlighting the need for additional public health interventions.