Abstract: This study explores the role and related molecular mechanism of Tianxiangdan (TXD) Capsules in ameliorating atherosclerosis (AS) by regulating GPER (G protein-coupled estrogen receptor) to inhibit NLRP3 inflammasome-mediated pyroptosis. Eight ApoE^-/^- mice were randomly selected and fed a normal diet as a blank control group, while the remaining ApoE^-/^- mice were induced with a high-fat diet to establish an atherosclerosis model. These mice were randomly divided into the following groups: model group, atorvastatin intervention group (3.03 mg/kg), TXD Capsules high-dose group (1.092 g/kg), medium-dose TXD group (0.546 g/kg), low-dose TXD group (0.273 g/kg), and medium-dose TXD plus GPER inhibitor (1 mg/kg) group. The effects of TXD Capsules on AS through GPER regulation and inhibition of NLRP3-mediated pyroptosis were evaluated by measuring the serum lipid profile, performing enzyme-linked immunosorbent assays, conducting histopathological analyses, and Western blot. The results showed that TXD significantly reduced serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and inflammatory cytokine levels while increasing high-density lipoprotein cholesterol (HDL-C) levels. TXD also reduced aortic plaque area and lipid deposition. In addition, TXD significantly upregulated GPER expression in aortic tissues and inhibited NLRP3 expression and pyroptosis. These effects were reversed by the GPER inhibitor. In conclusion, TXD may inhibit NLRP3 inflammasome-mediated pyroptosis by upregulating GPER expression, thereby alleviating inflammatory responses in the atherosclerotic microenvironment and exerting vasculoprotective effects.