<p>Hyperlipidemia represents a major global health concern, closely linked to cardiovascular disease (CVD) and metabolic syndrome. Effective regulation of blood lipid and cholesterol (CHO) is essential for preventing and managing this condition. Korean red ginseng (KRG), a traditional medicinal plant, exhibits diverse pharmacological properties, including antihyperlipidemic, immune-enhancing, anti-fatigue, and antistress effects. While previous studies suggest that KRG reduces lipid levels and may lower the risk of hyperlipidemia and CVD, its precise molecular mechanisms remain unclear. In this study, proteomic analysis revealed that KRG modulates proprotein convertase subtilisin/kexin type 9 (PCSK9) in the blood of KRG-administered rats. In hyperlipidemic animal models induced by Triton WR-1339 and a high-fat diet (HFD), KRG treatment significantly reduced total cholesterol (TCHO), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels. Furthermore, KRG regulated PCSK9 expression and low-density lipoprotein receptor (LDLR), key regulators of LDL metabolism, in hepatic tissues. These findings indicate that KRG exerts lipid-lowering effects by modulating PCSK9 and LDLR expression, thereby regulating cholesterol metabolism through the sterol regulatory element-binding protein 2 (SREBP2)/PCSK9/LDLR signaling pathway. This study establishes KRG’s potential as a novel therapeutic agent for preventing and managing hyperlipidemia and CVD.</p>