Heatstroke is a life-threatening acute condition characterized by dysregulated temperature control, resulting in high core temperature and multi-organ dysfunction. Despite extensive research, the molecular mechanisms underlying heatstroke-induced organ damage have not been fully elucidated. This review aims to summarize recent advancements in the field of heatstroke, focusing on etiological factors, organ damage, and molecular mechanisms. By exploring the intricate interplay between heat-related cytotoxicity, inflammatory response, and tissue dysfunction, this review offers insights for future research and clinical practice in managing heatstroke patients. Further investigations are warranted to elucidate the specific mechanisms of organ damage and improve treatment strategies for heatstroke.