The target of this novel work is to assess the immunosuppression, genotoxicity, histopathological alterations, and cumulative mortality induced by acute toxicity of magnetite nanogel (MNG) in Nile catfish. Furthermore, a subsequent 10-day depuration period is adopted to estimate the restoration of those disturbed indices. Nile catfish (n = 180) were allotted into four groups and exposed to different concentrations of MNG (0, 1/10, 1/8, and 1/5 96-h LC50). The outcomes displayed a remarkable concentration-dependent decline in the immune indices level (LYZ, NO, and MPO). The gene expression of antioxidant (SOD) and apoptosis-regulatory genes (MAPK3 and JNK) was upregulated in MNG-exposed fish. Histopathological disruptions in the tissue architecture of gills and intestines were also evident in MNG-exposed groups. Interestingly, after a 10-day depuration period, marked improvement in the level of immune response mediators and gene expression of apoptotic genes was evident in all experimental groups, particularly at 1/10 of LC50. Overall, exposure to higher concentrations of MNG (1/5 and 1/8 of LC50) exerts multiple adverse influences on the Nile catfish, which were less pronounced at 1/10 of LC50. Surprisingly, a subsequent 10-day recuperation time was adequate for alleviating those impairments, with the maximum improvement in the Nile catfish exposed to 1/10 of LC50