The aim of the paper is to predict heat stress of human wearing chemical protective clothing (CPC). A proposed human thermal model was applied to simulate the core and skin temperatures with inputs of human activity level, clothing properties, and environmental conditions. Manikin tests were conducted to measure the thermal insulation and evaporative resistance of clothing which were two important inputs of the thermal model. The core temperature was predicted as an indicator of heat stress to evaluate the maximum exposure time. The effects of ambient temperature, relative humidity, and metabolic rate on core temperature, skin temperature, and maximum exposure time were analyzed. It was found that metabolic rate and ambient temperature had a greater effect on the skin temperature, core temperature and maximum exposure time than the relative humidity. Additionally, the effects of ambient temperature and metabolic rate on core and skin temperatures were slightly greater in humid environments than in dry environments. The model is capable of predicting maximum exposure time in different clothing systems under various environmental conditions and can provide an instruction for the design of CPC.