||The present study first time scrutinized the lipid lowering effect of ethanolic seed extract (ESEt) of Centratherum anthelminticum in high-fat diet (HFD) induced hyperlipidemic rabbits. ESEt was used to determine acute toxicity in overnight fasted normal rabbits while its effect on biochemical parameters including serum total cholesterol (TC), triglycerides (TG), high (HDL-c), low (LDL-c), very low-density (VLDL-c) lipoproteins, antiatherogenic index (AAI), alanine aminotransferase (ALT), catalase (CAT), creatine kinase (CK), lipase, lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and HMG-CoA/mevalonate ratio were estimated in HFD induced hyperlipidemic animal model. ESEt (10-2000 mg/kg) showed no sign of acute toxicity in rabbits. Similarly, three doses (200, 400, & 600 mg/kg) of same extract induced significant reduction in serum levels of TC, TG, LDL-c, VLDL-c and an increase in HDL-c level with improvement in AAI found in test groups. Normal ALT and CK levels were also observed with positive progress found in antioxidant enzymes status, HMG-CoA / mevalonate ratio and lipase activity. Results conclude that ESEt exhibits antihyperlipidemic and antioxidant effects in HFD induced hyperlipidemic animal model.