Polygoni Multiflori Radix dose-dependently improved HFD-induced abnormalities in mice (<i>p</i> < 0.05 or <i>p</i> < 0.01).<h4>Conclusions</h4>Polygoni Multiflori Radix effectively improves HFD-induced dyslipidemia by regulating the AMPK/SREBP-2/PCSK9/LDLR pathway to ameliorate hepatocyte lipid metabolism and reduce oxidative stress/liver injury. The gene discussed is LDLR; the disease is metabolic syndrome.