This study was conducted to evaluate the antioxidative and immunity roles of diets supplemented with ChNP and vitamin C on Oreochromis niloticus against sublethal Imidacloprid (IMID) toxicity effects. A total of healthy 210 tilapia fish (average initial weight 21.21 ± 0.05 g) were separated into seven groups: The first group reared on clean water and were fed a basal diet (control group which was called group C). The other six fish groups were stocked in water contaminated with sublethal IMID concentration (0.01 μg L−1) and fed supplemented diets as follows: IMID (basal diet), ChNP (5 g ChNP kg−1 diet), VC1 (250 mg vitamin C kg−1 diet), VC2 (250 mg vitamin C kg−1 diet), ChNP+ VC1 (5 g ChNP +250 mg vitamin C kg−1 diet), and ChNP+ VC2 (5 g ChNP +500 mg vitamin C kg−1 diet). The results indicated significant enhancement in all growth-performance parameters, body indices, and Survival Rates (SR) by the dietary-combined ChNP and vitamin C levels. Additionally, a diet supplemented with a combination of ChNP and vitamin C (ChNP+VC1 and ChNP+VC2) significantly decreased imidacloprid residual concentration in fish tissue compared with the IMID group. A marked increment of both hematological and antioxidative enzymes and innate immunity parameters were fortified with dietary ChNP supplementation combined with high vitamin C levels. The liver histopathological examination showed a clear improvement in all treated groups and seemed to be a normal structure in the dietary-combined ChNP and vitamin C groups. In conclusion, the combined dietary supplementation of ChNP and vitamin C exerted a beneficial health effect against imidacloprid toxicity in tilapia.