Proprotein convertase subtilisin/kexin type 9 (PCSK9) is mainly expressed in the liver and contributes to cholesterol homeostasis. PCSK9 binds to the epidermal growth factor (EGF), a domain of the LDL receptor (LDLR). PCSK9 promotes degradation of these cell surface LDL receptors. Albeit the efficacy of statin therapy, some patients with familial hypercholesterolemia, an inherited autosomal dominant disorder characterized by extremely high levels of LDL‐C face substantial residual risk associated with high levels of LDL-C since statin therapy is not completely successful in lowering LDL-C levels, particularly in heterozygous or homozygous familial hypercholesterolemia patients. Hence, inhibition of PCSK9 has emerged as an attractive target to control LDL-C levels. Two antibody-based drugs that directly target PCSK9 were approved by United State Food and Drug Administration (USFDA) in 2015 and several more candidates are undergoing clinical trials. So far, there are only a few reports regarding natural products with PCSK9 inhibitory activity. During our search for PCSK9 modulatory compounds from medicinal plants, we found that sauchinone from Saururus chinensis downregulated PCSK9 expression. In the present study, it was found that the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) was downregulated, and the expression of LDLR was upregulated in sauchinone-treated HepG2 cells. Consequently, LDL-C uptake was increased. As a transcriptional factor of PCSK9 expression, SREBP-2 was proposed by transcriptome analysis and western blotting. In obese mice administered orally, sauchinone increased hepatic LDLR through PCSK9 inhibition and showed the reduced serum LDL-C levels and downstream targets of SREBP-2.