The　objective　of　this　study　was　to　investigate　the　effects　of　simvastatin　(SIM)　on　lipid　metabolism　disorders　and　gut　microbiota　in　high-fat　diet-induced　hyperlipidemic　rats.　The　obtained　results　revealed　that　feeding　rats　with　SIM　(20　mg/kg/day)　significantly　decreased　serum　lipid　level　and　inhibited　hepatic　lipid　accumulation　and　steatosis.　Histological　analysis　further　indicated　that　SIM　reduced　lipid　deposition　in　adipocytes　and　hepatocytes　in　comparison　with　that　of　the　HFD　group.　The　underlying　mechanisms　of　SIM　administration　against　HFD-induced　hyperlipidemia　were　also　studied　by　UPLC-Q-TOF/MS-based　liver　metabonomics　coupled　with　pathway　analysis.　Metabolic　pathway　enrichment　analysis　of　liver　metabolites　with　significant　difference　in　abundance　indicated　that　fatty　acids　metabolism　and　amino　acid　metabolism　were　the　main　metabolic　pathways　altered　by　SIM　administration.　Meanwhile,　operational　taxonomic　units　(OTUs)　analysis　revealed　that　oral　administration　of　SIM　altered　the　composition　of　gut　microbiota,　including　Ruminococcaceae　(OTU960)　and　Lactobacillus　(OTU152),　and　so　on.　Furthermore,　SIM　treatment　also　regulated　the　mRNA　levels　of　the　genes　involved　in　lipid　and　cholesterol　metabolism.　Immunohistochemistry　(IHC)　analysis　of　the　liver-related　proteins　(CD36,　CYP7A1　and　SREBP-1C)　showed　that　oral　administration　of　SIM　could　regulate　the　levels　of　the　protein　expression　related　to　hepatic　lipid　metabolism.　©　Copyright　©　2020　Zhang,　Fan,　Ye,　Hu,　Zheng,　Shi,　Cheng,　Lv,　Chen　and　Liang.