This experiment was carried out to investigate the effects of ZnO nanoparticles (ZnO NPs) on metabolic parameters, oxidative stress, apoptosis, and pathophysiological alterations of the pancreas in diabetic rats. Nanoparticle was synthesized and its characterizations were determined. We evaluate the toxicity and useful dosage of the ZnO NPs in Wistar male rats. Our experiment showed that 5 mg/kg had a useful effect and was not toxic. Hence, in the next step, the Wistar male rats were randomly divided into 3 groups as follows: (1) control rats (C); (2) diabetic rats (D), (3) diabetic rats received 5 mg/kg NP. After 4 weeks, animals were sacrificed, and blood chemical factors were measured. The oxidative stress, inflammatory, and apoptosis pathways were evaluated. Insulin and glucagon-like peptide-1 (GLP-1) mass was evaluated by immunofluorescence. The morphological changes were evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, hematoxylin and eosin (H&E), and aldehyde fuchsin. ZnO NP acts as an insulin sensitizer and normalizes blood glucose, GLP-1 levels as well as apoptosis, oxidative stress, and inflammatory pathway gene expression in diabetic rats. ZnO NP also alleviates the pathological alterations in the pancreas. This study showed that a low dose of ZnO NPs protects pancreatic β cells from oxidative stress and apoptosis. Administration of ZnO NP also normalized the pathophysiological alteration of the pancreas, thus normalizing metabolic abnormality.