Hand-foot-mouth disease (HFMD) is an emerging infectious disease that affects thousands of children every year in Vietnam, especially in the Mekong Delta Region (MDR). This study aims to analyse both provincial and regional level effects of climate factors on HFMD in multiple provinces of this high-risk region. Generalized linear models were used to analyse the daily effects of average temperature, humidity and rainfall on HFMD incidence in each province (provincial-level effects), and random-effect meta-analysis was used to estimate the pooled effect size of these climate–HFMD associations (regional-level effects). Daily effects of the climate factors on HFMD were found at both provincial level and regional level. At provincial level, temperature and humidity had statistically significant positive associations with HFMD while rainfall had both positive and negative associations with HFMD at different lag days. At regional level, temperature and humidity were positively associated with HFMD at lag 0 days (1.7%; 95%CI 0.1%–3.3%) and at lag 3 days (0.3%; 95%CI 0.1%–0.5%), respectively. In contrast, rainfall was found to be negatively associated with HFMD at lag 5 days (− 0.3%; 95%CI − 0.4% to − 0.1%). Heterogeneities of the effects of rainfall on HFMD were found to be higher than those of temperature or humidity. This is the first study to address the climate–HFMD associations in multiple provinces of the MDR. These associations draw attention to climate-related health issues and will help in developing an environment-based early warning system for HFMD prevention and control.