The current study is a new approach for investigating the ameliorative effects of chia seeds powder (CSP) (Salvia hispanica) against haemato-biochemical dysfunction, oxidative stress, and DNA damage induced by zinc oxide nanoparticles (ZnONPs) in Oreo chromis niloticus. Four fish groups were allocated in triplicates as follows: group I-control, group II-treated with 10g/kg diet CSP, group III-exposed to 1/20 LC50 of ZnONPs, and group IV-exposed to 1/20 LC50 of ZnONPs+10g CSP/kg diet for 30 days. Blood, liver, and kidney tissue samples were collected at the end of the experiment for haemato-biochemical, oxidative stress biomarkers, and DNAdamageevaluations. Results revealed that CSP administration significantly ameliorated the ZnONPs toxic effect. Where, CSP effectively increased WBCs, and serum total proteins, albumin, globulin, and immune parameters (IgG, IGM, and lysozyme [LYZ] activity), which were decreased after exposure to ZnONPs toxicity. In addition to the prominent ability of CSP to decrease the elevated levels of stress indicators (glucose and cortisol), liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), kidney products (creatinine and urea), catalase (CAT), superoxide dismutase (SOD), and hepato–renal lipid peroxidation (LPO) of Nile tilapia exposed to ZnONPs. Furthermore, CSP sustained the activity of the reduced glutathione (GSH), total antioxidant capacity (TAC), and WBCs, Hb, and Ht content were significantly declined in ZnONPs-exposed O. niloticus compared to the control group. Meanwhile, administration of 10g CSP/kg diet restored the hemato-biochemical profile and reduced oxidative damage induced by ZnONPs toxicity as the WBCs and hepatic DNA damage were significantlyincreased in exposed fish. The study suggested that CSP treatment has hepato-renal protective functions and antioxidative effect against ZnONPs toxicity in Nile tilapia