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Hand, foot, and mouth disease (HFMD) is the leading Category C infectious disease affecting millions of children in China every year. In the context of global climate change, the understanding and quantification of the impact of weather factors on human health are particularly critical to the development and implementation of climate change adaptation and mitigation strategies. The aim of this study was to quantify the attributable burden of a combined bioclimatic indicator (apparent temperature) on HFMD and to identify temperature-specific sensitive populations. A total of 123,622 HFMD cases were included in the study. The non-linear relationship between apparent temperature and the incidence of HFMD was approximately M-shaped, with hot weather being more likely to be attributable than cold conditions, of which moderately hot accounting for the majority of cases (21,441, 17.34%). Taking the median apparent temperature (19.2 °C) as reference, the cold effect showed a short acute effect with the highest risk on the day of lag 0 (RR = 1.086, 95% CI: 1.024 ~ 1.152), whereas the hot effect lasted longer with the greatest risk at a lag of 7 days (RR = 1.081, 95% CI: 1.059 ~ 1.104). Subgroup analysis revealed that males, children under 3 years old, and scattered children tended to be more vulnerable to HFMD in hot weather, while females, those aged 3 ~ 5 years, and nursery children were sensitive to cold conditions. This study suggests that high temperatures have a greater impact on HFMD than low temperatures as well as lasting longer, of particular concern being moderately high temperatures rather than extreme temperatures. Early intervention takes on greater importance during cold days, while the duration of HFMD intervention must be longer during hot days. [ABSTRACT FROM AUTHOR]