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The human body interacts with the changing environment and tries to maintain its body core temperature within a narrow temperature range of 37 ± 0.5 °C. The transfer of heat and moisture between the human body and its surrounding environment depends on many factors, e.g., environmental conditions, the activity level of the human body, and clothing characteristics. Among these factors, clothing properties are the only one that can be managed according to their end use. Since clothing acts as an interface and barrier, it has a great influence on the thermal transmission between the human body and the environment, which is in turn essential for high wear comfort. This work proposes innovative simulation techniques to generate a comprehensive solution for evaluating the thermophysiological parameters of the human body as well as the thermal comfort of different textile materials. This simulation considers the mechanical and thermal properties of clothing, which both have a great influence on fit and non-uniform air gaps between clothing and human body. This simulation process offers a fast, intelligent, and qualitative design solution for sectors involving outdoor, work, and safety clothing as well as sportswear, which is required in this rapidly developing and advanced technological era.