This study was conducted to investigate the effect of milk thistle powder (MTP) and/or co-enzyme Q10 (CoQ10) dietary supplementation on the neurobehavioral performance and brain oxidative status and histological picture in Nile tilapia (Oreochromis niloticus) reared in nickel (Ni)-polluted water. Eight groups of fish, each containing 30 fish (34.25 ± 1.02 g), were included. The experimental diets comprised basal diet, 10 g MTP/kg fortified diet, diet containing 40 mg CoQ10/kg, or MTP + CoQ10 supplemented diet. Four fish groups were cultivated in non-polluted water, and the other four groups were reared in water containing 3.6 mg Ni /L water. The trial continued for 40 days. The results revealed that MTP and/or CoQ10 addition to the O. niloticus diets significantly (P < 0.001) reversed the Ni-induced reduction in feeding frequency, middle swimming behavior, and the number of middle crossing. But, the Ni-induced aggression in terms of increased approach, chasing, fin tugging, fleeing, and mouth pushing were significantly (P < 0.001) reduced with MTP and/or CoQ10 dietary supplementation. Also, the significant (P < 0.001) depletion in the enzymatic (catalase, superoxide dismutase, glutathione peroxidase, and glutathione S transferase) and non-enzymatic (reduced glutathione) antioxidant brain content recorded in Ni-exposed fish was significantly (P < 0.001) restored by MTP and/or CoQ10 addition to their diets. Moreover, the Ni-induced significant (P < 0.001) increments in malondialdehyde content and Ni brain content of fish were significantly (P < 0.001) diminished by MTP and/or CoQ10 dietary supplementation. In addition, MTP and/or CoQ10 supplementation to O. niloticus diets significantly (P < 0.001) restored the Ni-induced depletion in acetyl-cholinesterase content in their brains. Moreover, the Ni-induced histopathological aberrations in the fish brain tissue, including choroiditis, multifocal encephalomalacia, myelencephalon neurons demyelination and vacuolation, Purkinje cell degeneration, and mesencephalon neuronal degeneration, were substantially revered by MTP and/or CoQ10 dietary supplementation. The MTP and CoQ10 co-addition to the O. niloticus diets attained the best neurobehavioral performance and brain oxidative status. These results concluded that MTP and/or CoQ10 could be considered as a beneficial dietary supplement for mitigating the Ni-induced negative impacts on the behavior and brain of the Nile tilapia.