Background <p>Postmenopausal women are at an increased risk for atherogenesis. Panax quinquefolium saponin (PQS) has demonstrated beneficial effects on decreasing inflammatory response, alleviating oxidative stress and improving endothelial function. However, the effect of PQS on atherogenesis in postmenopausal women remains unknown. This study explored the effects of PQS on different pathological stages (8 or 14&#xa0;weeks) of atherogenesis in ApoE^−/− mice with mimicking postmenopausal condition by ovariectomy.</p> Methods <p>Atherosclerotic plaque, levels of serum inflammatory cytokines and apoptosis of aortic endothelium were detected. Human umbilical vein endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (ox-LDL) were used to investigate the mechanism. Using network pharmacology, molecular docking and receptor inhibitor to explore the target of PQS in ovariectomized ApoE^−/− mice.</p> Results <p>ApoE^−/− mice subjected to ovariectomy displayed an increase in atherosclerotic plaque formation, levels of serum inflammatory cytokines and apoptosis of aortic endothelial cells. PQS treatment counteracted these detrimental effects both at 8 and 14&#xa0;weeks. Network pharmacology and molecular docking analysis revealed that PQS targeted estrogen receptor α (ERα) in ovariectomized ApoE^−/− mice, a key regulator in inflammation and aortic endothelial apoptosis. PQS regulated inflammation and apoptosis via ERα/PI3K/Akt and ERα/MEK/ERK1/2 pathways. ERα inhibitor mostly counteracted the beneficial effects of PQS on ovariectomized ApoE^−/− mice and injured HUVECs, in contrast, ERα activator enhanced these effects.</p> Conclusions <p>The study indicated that PQS decreased atherosclerotic plaque by reducing inflammation and apoptosis of aortic endothelium in ovariectomized ApoE^−/− mice via regulating ERα, providing new insights into PQS as a therapeutic target in postmenopausal atherosclerosis.</p> Graphical abstract <p></p>