Hyperlipidemia is a heterogeneous disorder characterized by an increased in triglycerides (TG) and low-density lipoprotein-cholesterol (LDL-C), as well as by a reduced plasma high-density lipoprotein cholesterol (HDL-C) level. The present study aimed mainly to demonstrate the therapeutic effects of 10-Dehydrogengardione (10-DHG), caffeic acid (CA) or Lycopene (LYC) on diabetic hyperlipidemia state referring to the role of ATP citrate lyase (ACLY) inhibition. Rats were randomly assigned into 6 groups, one group received normal chow diet (normal control); the other groups received streptozotocin (STZ) intraperitoneal and then fed on CCT diet for 2 weeks and continue later for 6 weeks. The second group received no treatment and referred to as diabetic hyperlipidemic control, the other three groups received ATOR (50 mg/kg/day), 10-DHG (10 mg/kg/day), CA (50 mg/kg/day) or LYC (20 mg/kg/day) subsequently and orally for 6 weeks. Serum and tissue samples were collected for biochemical and histological evaluations. DHC rats demonstrated significant hyperglycemia, dyslipidemia, increased hepatic tumor necrosis factor- alpha (TNF-α), malondialdehyde (MDA) and remarkable increase in hepatic ACLY, 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase and fatty acid synthase (FAS). However, hepatic reduced glutathione (GSH) and phosphorylated form of AMP-activated protein kinase (AMPK-P) activities showed significant decrease. Administration of either ATOR, 10-DHG, CA or LYC induced significant hypoglycemic and hypolipidemic effects; decreased hepatic levels of TNF-α, MDA, ACLY, HMG-CoA reductase and FAS along with GSH and AMPK-P increases. Histopathological findings showed clear correlation with the biomarkers results. Collectively, the findings of this study suggest that hypolipidemic effects of certain natural products having inhibitory effect on ACLY activity may be a promising therapeutic strategy to ameliorate hyperlipidemia that proceeded ATOR and may be other traditional hypolipidemic drugs.