Recently, toxicity with heavy metals has been a major health issue because of its detrimental impact on fish and fish consumers. Different from previous studies, here we are the first trial to assess the impending effect of the watery solution of magnetite (Fe3O4) nano gel (MG) against toxicity of lead (Pb) in African catfish (Clarias gariepinus). The evaluation included recording ethology, brain function, antioxidant traits, gene expression plus histopathological/and immunohistochemical assessment and residues in the brain tissues. Fish (n = 160; Bwt: 100.00 ± 7.39 g) were randomly allotted into four groups (40/group; 10 fish per replicate; four replicates/ group). The first group (control) was not exposed to MG or lead chloride (PbCl2 as a source of Pb). The second (MG) group was exposed to 1.2 mg/L of MG. The third group (Pb) was subjected to PbCl2 (69.30 mg/L) toxicity. Meanwhile, the fourth group (MG + Pb) was subjected to PbCl2 toxicity (69.30 mg/L) and at the same time, treated with 1.2 mg/L of MG. The trial lasted for 45 days. The exposure to Pb resulted in notable ethological alterations (unusual swimming, surfacing, loss of equilibrium, laterality, and spiral movement). A clear decline in serum antioxidant parameters (catalase, reduced glutathione content, and total antioxidant capacity) and brain neurotransmitter (acetylcholine esterase) was observed in the Pb-exposed fish. An up-regulation of the myeloid differentiation factor 88 (MyD88), heat shock protein 70 (HSP70), and toll-like receptor (TLR-1 and TLR-5) genes of the brain plus higher residual Pb deposition in brain tissues were induced by Pb exposure. Additionally, prominent histopathological lesions including neuronal degeneration and vacuolation as well as a strong caspase- 3 and a weak B-cell lymphoma 2 (bcl-2) immune expression were obvious in the brain. Remarkably, the addition of MG in water induced an improvement in these biomarkers and retrieved the histopathological changes. Considering these outcomes, MG is a promising candidate and an innovative approach as antitoxic against the toxicity of Pb for sustaining the performance and health of African catfish.