This study aimed at the evaluation of the mitigating effects of dietary zeolites (ZEO) and/or chitosan nanoparticle (ChNP) on imidacloprid (IMID)-induced toxicity in Nile tilapia (Oreochromis niloticus). Fish (18.03 ± 0.01 g) were allocated into six groups; one fed on a basal diet (control) (CTR), and the other groups were fed diets supplemented with ChNPs (5 g kg−1) and/or ZEO (20 and 40 g kg−1) (ZEO20 and ZEO40) for 60 days. In the last 14 days of the experiment, all groups were exposed to a sub-lethal dose of IMID (½ of 96 h LC50 = 0.0545 μg L−1). Dietary ZEO20 significantly improved all growth parameters (P ˂ 0.05), while ChNPs had no significant effects. The crude protein of the fish body was significantly increased in all groups compared to the CTR (P ˂ 0.05). No significant impacts of ChNPs, ZEO, and their interaction (P > 0.05) were noticed on the moisture, dry matter, and ash percentages. Compared to the CTR, hematocrit values were significantly decreased (P ˂ 0.05) in ChNP and ZEO20 groups; meanwhile, their levels were significantly increased (P ˂ 0.05) in the ZEO40 group and all combined treatments. Fish fed diets with ChNPs and/or ZEO had significant increments in the MCV values (P ˂ 0.05). Moreover, fish fed diets supplemented with ChNPs or their combination with ZEO had the lowest glucose and alkaline phosphatase levels compared with the CTR. Serum aspartate transferase levels were significantly decreased in all treated groups (P ˂ 0.05) compared to the CTR. ChNPs alone or combined with ZEO significantly exhibited the highest lysozyme and nitro blue tetrazolium values (P ˂ 0.05). On the other hand, fish in the CTR group had the highest malondialdehyde and lowest nitric oxide levels compared to the other groups. Interestingly, the lowest IMID residues in fish flesh were found in fish groups fed diet with a combination of ZEO and ChNPs. Partial or complete protection of the hepatic and splenic tissues were observed in fish group with combined treatment with ChNPs and ZEO. In conclusion, the application of ZEO and/or ChNPs in Nile tilapia diets looks to be a leading approach to mitigate the toxic impacts of IMID.