Polycystic ovary syndrome (PCOS) presents itself as a multifaceted disorder affecting the reproductive, endocrine, and metabolic systems, with enduring complications. Although the intricate mechanisms behind the condition's pathology remain mostly obscure, the primary culprits seem to revolve around hyperandrogenism, insulin resistance, and oxidative stress. Within the realm of disease therapies, Zinc oxide nanoparticles (ZnONPs) hold significant potential for numerous applications, including insulin resistance. This study evaluated the role of ZnONPs alone and when combined with metformin in Letrozole- induced PCOS. Methods: PCOS was induced in rats using a 36 days-course of letrozole; ZnONPs or/and metformin were given from day 22 for 15 days. Results: PCOS group resulted in a significantly higher body weight, ovarian weight as well as elevated testosterone, insulin, glycemia and lipid profile levels. All of these effects were significantly reduced by ZnONPs. Besides, ZnONPs remarkably inhibited the letrozole induced oxidative stress in the ovaries by reducing the upraised malondialdhyde and increasing the suppressed superoxide dismutase and glutathione peroxidase activities. ZnONPs were able to reduce ovarian tissue CYP17A1 expression, the key in androgen biosynthesis that was significantly higher in PCOS group. Ovarian histopathological examination confirmed the biochemical findings. Conclusion: The outcomes of this study indicated that ZnONPs might hold great promise in addressing PCOS impairments through multiple mechanisms. By reducing insulin resistance, hyperandrogenism, and improving redox status. When combined with metformin, they could synergistically enhance control over the condition.