ABSTRACT Geraniin (GE), an ellagic tannin extracted from Geranium wilfordii , has been demonstrated to improve high‐fat diet‐induced metabolic disorders. This study aimed to investigate the effect of Geraniin on atherosclerosis and the underlying mechanism. In this study, we used the ApoE −/− mice as a model of atherosclerosis. We fed the ApoE −/− mice a high‐fat diet containing 1.25% cholesterol and treated them with or without 5 or 10 mg/kg body weight of GE for 10 weeks. Meanwhile, we combined network pharmacology analysis to explore how GE improves H 2 O 2 ‐induced endothelial cell apoptosis and inflammatory response. Our results showed that GE treatment significantly reduced serum concentrations of lipids, oxidative stress damage, lipid deposition, and atherosclerotic plaque lesions in the ApoE −/− mice. Furthermore, a network pharmacology analysis indicated that the beneficial effect of GE treatment on atherosclerosis is closely related to its effect on oxidative stress, cell apoptosis, and inflammatory responses. We also showed that in H 2 O 2 ‐treated HUVEC cells, GE promoted the release of NO, increased the activity of antioxidant enzymes, reduced endothelial cell apoptosis, reduced the production of inflammatory cytokines IL1β, IL6, and TNFα, and activated the Akt/eNOS/NO and GSK‐3β/Nrf2/HO‐1 signaling pathways. Taken together, these findings demonstrate that GE can alleviate high‐fat diet‐induced atherosclerosis in ApoE −/− mice by inhibiting oxidative stress‐induced endothelial cell apoptosis and inflammation.