As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic understanding of its action is lacking. Here, we found that atorvastatin counteracted angiotensin II-induced vascular endothelial injury in mice with hypertension. Mechanistically, atorvastatin up-regulated WWP2, a E6AP C-terminus (HECT)-type E3 ubiquitin ligase with an essential role in regulating protein ubiquitination and various biological processes, thereby rescuing vascular endothelial injury. By ubiquitinating ATP5A (ATP synthase mitochondrial F1 complex subunit alpha), WWP2 degraded ATP5A via the proteasome pathway, stabilizing Bcl-2/Bax in the mitochondrial pathway of apoptosis. Moreover, atorvastatin further ameliorated death of vascular endothelial cells and improved vascular endothelial functions under WWP2 overexpression, whereas WWP2 knockout abrogated these beneficial effects of atorvastatin. Furthermore, we generated endothelial cell-specific WWP2 knockout mice, and this WWP2-mediated mechanism was faithfully recapitulated in vivo. Thus, we propose that activation of a WWP2-dependent pathway that is pathologically repressed in damaged vascular endothelium under hypertension is a major mechanism of atorvastatin. Our findings are also pertinent to develop novel therapeutic strategies for vascular endothelial injury-related cardiovascular diseases.