ABSTRACT With global warming in recent years, humans have been subjected to the impact of thermal environments on both work and life. Improving the body's ability to withstand heat is an urgent task. Accordingly, we summarize the signaling pathways in response to heat and the effects of heat stress on related physiological processes, such as mitochondrial health, inflammation, oxidative stress, and apoptosis, which provide a theoretical basis for understanding the damaging effects of a thermal environment. Based on this, we further summarize the multi‐organ injury caused by heat stress and its specific pathophysiological mechanisms to provide advice on coping strategies for people who need to perform physical activity or sports in a hot environment. In summary, this study provides research targets for future clinical research and ideas for practical application by summarizing the physiological and pathological processes and current coping strategies under heat stress.