Abstract: Heatstroke (HS) is a life-threatening condition characterized by central nervous system dysfunction and severe hyperthermia, which can rapidly progress to multiple organ dysfunction syndrome (MODS) and death. The pathogenesis of HS shares similarities with that of sepsis. NETosis, a unique form of neutrophil cell death, plays a central role in sepsis; however, its role in HS remains understudied and underappreciated. This review summarizes the current understanding of the role of NETosis in HS and HS-induced MODS. Furthermore, we discuss the scientific rationale and future prospects of targeting the NETosis pathway as a potential therapeutic strategy, with the goal of providing a theoretical foundation for elucidating the pathogenesis of HS and developing novel interventions.