Type-2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance followed by pancreatic islet Beta-cell failure. Inflammation plays a crucial role in both insulin resistance and pancreatic Beta-cell failure. Salicylates and pioglitazone are known to have antidiabetic effect and are used for treatment of type 2 diabetes (T2D). This experiment was designed to investigate the antidiabetic effect of low and high doses of salicylates either alone or in combination with pioglitazone. Seventy male albino rats were randomly divided into seven groups: control, untreated diabetic, diabetic treated with low dose of salicylates (10 mg /kg/day), diabetic treated with high dose of salicylates (120 mg/kg/day), diabetic treated with pioglitazone (10 mg /kg/day), diabetic treated with both low salicylates and pioglitazone and diabetic treated with both high salicylates and pioglitazone. T2D was induced following 12 weeks high fat and high fructose (HFHF) dietary protocol. Both low and high doses of salicylates alone or in combination with pioglitazone ameliorate hyperglycemia, hyperlipidemia, insulin resistance, reduced the level of proinflammatory cytokines and increased adiponectin with activation of PPAR-γ and inhibition of NF-kβ. Co-administration of salicylates and pioglitazone was more effective in improving overall metabolic parameters compared to each of the monotherapy. Collectively, administration of acetylsalicylic acid, even at low doses, has the ability to potentiate the PPAR-γ agonist pioglitazone suggesting a new combination for therapeutic applications.