Lipopolysaccharide is an endotoxin derived from gram-negative bacteria and its pathophysiology has been linked to septicemia and fatty liver among other multiple organ toxicity. This study was designed to investigate the ameliorative effect of Hesperetin and Ellagic acid against LPS-induced perturbation on glycolytic and mitochondrial metabolizing enzymes. Eighteen Balb/c albino mice were assigned into three groups of six mice each: Group A (control) received olive oil and DMSO orally for 28 days, group B received LPS (250 µg/kg/BW) intraperitoneally for 14 days. Group C were pre-treated with Hesperetin (40 mg/kg/BW) and Ellagic acid (30 mg/kg/BW) orally for 14 days prior to co-administration of LPS (250 µg/kg/BW) for another 14 days. The mice were sacrificed, blood was collected into heparinized tubes while liver, kidney, and spleen were excised. Glycolytic enzyme and mitochondrial metabolizing enzymes activity were assayed in the kidney, liver, spleen, plasma, erythrocytes, and lymphocytes. Results are expressed as mean±SEM. The level of homogeneity among the groups was assessed using analysis of variance (ANOVA). There was a significant (P< 0.05) down-regulated activities of hexokinase, aldolase, lactate dehydrogenase, and NADase when compared with control. Also, activities of mitochondrial metabolizing enzymes (succinate dehydrogenase, malate dehydrogenase, combined complexes I+ III, II+ III, and IV) were all significantly (P< 0.05) deceased relative to control. Ellagic acid and hesperetin ameliorated glyco-metabolic perturbations induced by exposure to lipopolysaccharide which has been correlated with risk factors for various metabolic disorders. Data from this study indicates that the use of ellagic acid and hesperetin ameliorate glyco-metabolic toxicity associated with Lipopolysaccharides.