The current study addresses the influence of Moringa oleifera leaves nanoparticles (MO-NPs) on growth, biochemical, immunological, and hepatic antioxidant alterations induced by zinc oxide nanoparticles toxicity in Nile tilapia (O. niloticus). Fish (N = 180) were divided into four groups with replicates. The first one was set as a control group and the second group was fed an MO-NPs-enriched diet (2.5 g/kg diet). The third group was exposed to 8 mg/L ZnO-NPs, while the forth group was exposed to 8 mg/L ZnO-NPs and fed on MO-NPs (2.5 g/kg diet) for 2 months. Exposure of O. niloticus to 8 mg/L ZnO-NPs induced the following consequences: a sharp decrease in the growth parameters; a marked increment in the biochemical biomarkers (glucose, cortisol, and liver enzymes (ALT, AST, ALP); a significant increase in serum renal products, urea and creatinine, cholesterol, and LDH levels. Nonetheless, the dietary MO-NPs supplementation for 2 months significantly alleviated the ZnO-NPs toxicity and significantly enhanced the growth indices, plus normalizing the physio-biochemical levels in the exposed group to ZnO-NPs toxicity to reach the levels of the control group. The MO-NPs markedly improved hepatic antioxidant biomarkers, MDA, and TAC, while, decreasing SOD, CAT, and GSH levels to be near the control values. Moreover, supplemented fish in MO-NPs (2.5 g/kg diet) and exposed to ZnO-NPs provided a remarkable increase in the immune profile (respiratory burst (RB) activity, lysozyme, and total immunoglobulins (IgM)) compared to the ZnO-NPs-intoxicated group. Based on the findings of the study, the exposed O. niloticus to ZnO-NPs were immune-antioxidant-depressed, besides showing growth retardation, and physio-biochemical alterations. On the other hand, a supplemented diet with MO-NPs is a novel approach to ameliorate ZnO-NPs toxicity for sustaining aquaculture and correspondingly protecting human health.