Obesity became a serious public health problem with enormous socioeconomicimplications among the Egyptian population. The present investigation aimed toexplore the efficacy of Zingiber officinale extract as a hypolipidemic agent com -bined with the commercially well- known anti- obesity drug simvastatin in obeserats. Thirty-five male Wister rats were randomly divided into five groups as fol -lows: group I received a standard balanced diet for ten weeks; high- fat diet wasorally administered to rats in groups II–V for ten weeks. From the fifth week to thetenth week, group III orally received simvastatin (40 mg/kg B.W.), group IV orallyreceived Z. officinale root extract (400 mg/kg B.W.), and group V orally receivedsimvastatin (20 mg/kg B.W.) plus Z. officinale extract (200 mg/kg B.W.) separately.Liver and kidney function tests, lipid profiles, serum glucose, insulin, and leptinwere determined. Quantitative RT-PCR analysis of PPAR-γ, iNOS, HMG- CoA re-ductase, and GLUT- 4 genes was carried out. Caspase 3 was estimated in liver andkidney tissues immunohistochemically. Liver and kidney tissues were examinedhistologically. The administration of Z. officinale extract plus simvastatin to high-fat diet-fed rats caused a significant reduction in the expression of HMG- coA re-ductase and iNOS by 41.81% and 88.05%, respectively, compared to highfat diet(HFD)-fed rats that received simvastatin only. Otherwise, a significant increase wasnoticed in the expression of PPAR- γ and GLUT- 4 by 33.3% and 138.81%, respec -tively, compared to those that received simvastatin only. Immunohistochemistryemphasized that a combination of Z. officinale extract plus simvastatin significantlysuppressed caspase 3 in the hepatic tissue of high- fat diet-fed rats. Moreover, thebest results of lipid profile indices and hormonal indicators were obtained whenrats received Z. officinale extract plus simvastatin. Z. officinale extract enhancedthe efficiency of simvastatin as a hypolipidemic drug in obese rats due to the highcontents of flavonoid and phenolic ingredients.K E Y W O R D Santi-obesity, caspase-3, GLUT-4, HMG-CoA reductase, RT-PCR, Zingiber officinale