The phenotypic transformation of vascular smooth muscle cells (VSMCs) and the occurrence of necroptosis may be the main pathological mechanisms of heat stroke -induced cardiovascular injury. However, the specific molecular mechanisms of VSMCs injury due to hyperthermia are currently unknown. The aim of this study was to evaluate the role of inhibitor RIPK1 (Nec-1) in phenotypic transformation and necroptosis of vascular smooth muscle cells induced by heat stroke. The results of in vivo and in vitro experiments consistently showed that high temperature induced a decrease in the expression of α-SMA and an increase in the expression of OPN in VSMCs, which induced the transformation of VSMCs from a contractile phenotype to a synthetic phenotype. At the same time, high temperature promoted the expression of RIPK1 and RIPK3 in VSMCs and activated necroptosis. Nec-1 inhibited the heat-induced high expression of RIPK1 and RIPK3. It also restored the expression of α-SMA and reduced the expression of OPN in VSMCs. These findings confirm the protective role of Nec-1 in heat stroke-induced necroptosis and phenotypic transformation of VSMCs.