Hand, Foot, and Mouth Disease (HFMD) is an infectious disease that primarily affects young children. In densely populated Jiangsu Province in China, the impact of extreme meteorological factors on HFMD is a concern. We aimed to examine the association between extreme meteorological variables and HFMD infection risk using daily HFMD infections and meteorological data from 2010 to 2017 in Jiangsu Province. We used distributed lag non‐linear model (DLNM) to analyze the data, which can effectively capture the nuanced non‐linear dynamics and lag effects in the relationship between HFMD and extreme meteorological factors. Comparing the 10th and 90th percentiles of meteorological variables with their respective median values, our results showed that extremely low temperatures and high humidity were significantly associated with increased HFMD infection risk. The greatest effect of extremely low temperatures was observed at a lag of 1–2 days, elevating the risk by 18 ∼ 33% (RR = 1.18 ∼ 1.33). Extremely high humidity was found to increase the risk of infection, starting at a lag of 4 days. In contrast, extremely high temperatures, low humidity, and high wind speed were associated with reduced risk of infection at lag of 0–12 days, with the range of RR values being 0.60–0.98 for extremely high temperatures, 0.69–0.89 for extremely low humidity, and 0.84–0.98 for extremely high wind speed respectively. Our findings suggest that extreme meteorological factors can significantly impact the incidence of HFMD in Jiangsu Province, and highlight the need for effective public health protection measures during the periods of extreme meteorological condition, particularly for vulnerable populations.