Background: Zinc oxide nanoparticles (ZnO NPs) are one of the most widely used engineered nanoparticles in industrial and consumer products, increasing exposure to these nanoparticles that may have harmful side effects. Aim of the Work: The aim of this work was to investigate subacute zinc oxide nanoparticles induced cytotoxicity, hepatotoxicity, nephrotoxicity, oxidative stress and genotoxicity in adult male albino rats. Material and Methods: Eighteen adult male albino rats were divided into two groups (9 rats per group); Group I served
as the control (vehicle) and Group II ZnO NP treated group (422mg/kg) for 2weeks via oral gavage. Thereafter Blood samples were collected and liver function tests (ALT,AST and ALP), kidney function tests (serum creatinine and urea) and serum MDA were determined. Then livers and kidneys were extracted to assess cell viability by trypan blue exclusion test, Zinc content, DNA fragmentation test (qualitative) and histopathological (H&E) and immuno histochemistry (caspase-3). Results: Oral ZnO NPs induced significant decrease in cell viability of liver and kidney, a significant elevation of zinc level in liver and kidney, serum liver enzymes, serum creatinine, urea and serum MDA. ZnO NPs produced DNA damage in liver and kidney. It also induced histopathological alterations in liver and kidney with moderate caspase-3 immunoreactivity. Conclusion: It can be concluded that ZnO NPs oral administration induced cytotoxic, hepatotoxic, nephrotoxic and genotoxic effects. Mechanism of ZnO NPs induced toxicity may be due to significant elevation of zinc level and lipid perioxidation.