Heavy metal toxicity is an important issue owing to its harmful influence on fish. Hence, this study is a pioneer attempt to verify the in vitro and in vivo efficacy of a magnetite (Fe3O4) nanogel (MNG) in mitigating waterborne lead (Pb) toxicity in African catfish. Fish (n = 160) were assigned into four groups for 45 days. The first (control) and second (MNG) groups were exposed to 0 and 1.2 mg L−1 of MNG in water. The third (Pb) and fourth (MNG + Pb) groups were exposed to 0 and 1.2 mg L−1 of MNG in water and 69.30 mg L−1 of Pb. In vitro, the MNG caused a dramatic drop in the Pb level within 120 h. The Pb-exposed group showed the lowest survival (57.5%) among the groups, with substantial elevations in hepato-renal function and lipid peroxide (MDA). Moreover, Pb exposure caused a remarkable decline in the protein-immune parameters and hepatic antioxidants, along with higher Pb residual deposition in muscles and obvious histopathological changes in the liver and kidney. Interestingly, adding aqueous MNG to Pb-exposed fish relieved these alterations and increased survivability. Thus, MNG is a novel antitoxic agent against Pb toxicity to maintain the health of C. gariepinus.