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Blood–brain barrier (BBB) leakage is an important cause of the exacerbation of pathological features of ischemia and reperfusion. However, the specific mechanism of cell death of vascular endothelial cells is not clear. It was found that ischemic reperfusion resulted in RIPK1 activation in vascular endothelial cells and induced cells to undergo subsequent RIPK1-dependent apoptosis (RDA). Inhibition of RIPK1 significantly reduced BBB breakdown and brain damage. The aim of this study is to investigate the mechanism of RIPK1 in the BBB leakage during the ischemia reperfusion procedure.In this study, the role of RIPK1 in the development of cerebral ischemia reperfusion injury (CIRI) was investigated by immunohistochemical approaches on KO or mutant mice. It was discovered by proteomics that autophagy activation resulting from ischemia and reperfusion significantly downregulated the level of A20 protein in vascular endothelial cells. A20 is an important protein that regulates RIPK1 and RDA. It was hypothesized that activation of autophagy in vascular endothelial cells caused by ischemic reperfusion led to a decrease in A20 protein, which, in turn, caused the activation of RIPK1 and the occurrence of RDA, leading to leakage of the blood–brain barrier. The findings in this study revealed the role of RIPK1 in vascular endothelial cell death and BBB leakage upon cerebral ischemia reperfusion injury (CIRI), and these findings provide a novel perspective for the treatment of ischemic reperfusion.