Objective: The extant study was designed to estimate the basic renotoxicity mechanism prompted by either alone or mixed treatments of zinc oxide nanoparticles (ZnO NPs) and mureer plant (Senecio glaucus L.) (SP), and to evaluate the prophylactic activity of gallic acid (GA) against them via examining biochemical, histological, and genetic studies in male rats for 30 days. Methods: Forty adult male rats were equally alienated into 8 groups with oral administrated; Control, GA (100 mg/kg), ZnO NPs (150 mg/kg), SP (400 mg/kg), GA+ZnO NPs (100,150 mg/kg), GA+SP (100,400 mg/kg), ZnO NPs+SP (150,400 mg/kg), and GA+ZnO NPs+SP (100,150,400mg/kg). Finally, blood and renal tissues were collected. Conclusion: Our results revealed that ZnO NPs and SP induced a significant increase in the concentrations of creatinine (CRE) and urea (URE), with the elevation of total lipid (TL) level compared to the control group, (p < 0.001). Also, they triggered congestion in the renal tubules, spreading of inflammatory cells, and degeneration in the lining epithelium. They also induced a strong immunoreactivity of caspase-3 expression. Conversely, GA alleviated and improved renal injury by controlling the presence of inflammatory cells. In conclusion, ZnO NPs and SP could be displayed as nephrotoxic and pro-apoptotic agents; yet,GA exhibits as a renoprotective and an anti-apoptotic agent.