Nowadays, nanomaterials are strongly introduced in the aquaculture sector as antidotal agents. Therefore, the current study aims to test magnetite ( Fe3O4) nano gel (MG) in relieving toxicity induced by lead (Pb) ions via assessment of stress condition, growth rate, oxidant/ antioxidant activity in serum, and histopathological lesions in gill tissue, plus different gene expressions in African catfish (Clarias gariepinus). Fish (n = 160) were haphazardly allotted into four groups (40/group; 10 fish per replicate) for 45 days. The first (control) and second (MG) groups were treated with 0 and 1.2 mg/L MG. The third (lead) and fourth (lead + MG) groups were treated with 0 and 1.2 mg/L MG, respectively, with exposure to lead chloride (69.30 mg/L). Findings showed that the exposure to lead resulted in a substantial increase in stress biomarkers (glucose and cortisol), plus the oxidant indicator (malondialdehyde) and a clear decline in the antioxidant parameters (superoxide dismutase and glutathione peroxidase) and growth indices (final body weight, weight gain, and specific growth rate). Additionally, there were prominent histopathological lesions in gill tissues including detached gill filaments and inflammatory cell infiltrates. The expression of inflammatory genes [transforming growth factor beta1 (TGF-β1), nuclear factor kappa beta 2 (NF-κβ2), interleukins (IL-1β and IL-8), and tumor necrosis factor-alpha (TNF-α)] showed a marked up-regulation with a down-regulation of the antioxidant gene [superoxide dismutase (SOD1)]. Surprisingly, the aqueous addition of MG in the lead-exposed group dismissed the serum biochemical changes with enhancement in the gills’ histological architecture, growth rate, and the expression of genes. Based on these results, MG (1.2 mg/L) is an innovative application as a safe antidotal agent against lead toxicity to sustain C. gariepinus’ health in the aquatic system and ensure the consumers’ safety.