Diabetes mellitus (DM) is a category of metabolic illness characterized by high blood sugar levels and insufficient pancreatic insulin production or activity within the body. The most common type of diabetes is type II diabetes, which is a metabolic condition characterized by insulin resistance and pancreatic islet β- cell failure, resulting in hyperglycemia. The goal of this study was to examine the anti-diabetic implications of zinc oxide nanoparticles (ZnO NPs) and/or pyrazolopyrimidine in type II diabetic rats. Rats with a weight of 150 ± 20 g were used. Animals were divided into five groups as follows: group 1: control, group 2: type II diabetic rats, group 3: diabetic rats received ZnO NPs (10 mg/ kg/orally/day), group 4: diabetic rats received pyrazolopyrimidine (5 mg/kg/orally/day), and group 5: diabetic rats received ZnO NPs (10 mg/kg/orally/day) + pyrazolopyrimidine (5 mg/kg/orally/ day), respectively, for 30 days. The results indicated that serum glucose, total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein-cholesterol (LDL-c), very low-density lipoprotein-cholesterol (VLDL-c), malondialdehyde, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha PGC-1α mRNA expressions were increased in the diabetic group versus the control group, while serum insulin, high-density lipoproteincholesterol (HDL-c), superoxide dismutase (SOD), and carnitine palmitoyltransferase 1A (CPT1A) mRNA expression levels were decreased. These parameters were reserved in the treated groups (ZnO NPs, pyrazolopyrimidine, and ZnO NPs + pyrazolopyrimidine). This study proved that ZnO NPs and pyrazolopyrimidine had an ameliorative effect on blood glucose levels, antioxidant status, lipid profile, liver function enzymes, and mRNA expression of hepatic genes