The dynamic mechanism of coping with stress at different body, organ, tissue and even cellular levels is a life critical process. Improving such capability means a better life quality. Oral supplementation of various therapeutics and natural agents has been widely implemented. Biomedical applications of nanomaterials have gained a lot of attention due to their extensive and important biological features and biomedical uses. All living beings require the trace metal zinc. Although, in the gut, dietary ZnO is poorly absorbed, zinc oxide nanoparticles (ZnO-NPs) can be considered a suitable substitution as it has an increased surface reactive area, bioavailability, and absorbability. The purpose of this study was to investigate the protective role of ZnO-NPs on metabolic and antioxidant activity after chronic application of multiple stressors. Forty adult male albino rats with initial mean body weight (200 ± 10) g were randomly divided into 4 equal groups (10 for each) as follow: Group one: control (Handled), Group two: Zinc oxide Nanoparticle (oral 3mg/kg Bwt ZnO-NPs), Group Three: Chronic restrain stress (CRS), Group Four: Chronic restrain orally administered with Zinc oxide nanoparticle (CRS + oral 3mg/kg Bwt ZnO-NPs). After 60 days of chronic restrain for 3 hrs/day, rats were sacrificed. Application of chronic restrain stress showed significant elevated in total cholesterol, triacylglycerol, corticosterone, MDA and glucose levels and reduced total antioxidant capacity, free fatty acid in comparison with control group. Oral administration of ZnO-NPs in chronic stressed rats significantly reduced Total Cholesterol, Free fatty acid, corticosterone, MDA, glucose levels and improved HDL-c, total antioxidant capacity and insulin levels compared to stressed group. Overall, ZnO-NPs administered orally may improve the body's antioxidant and metabolic functions.