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We investigated the effects of dietary enriched with Shilajit in three dose levels: 2.0, 4.0, and 6.0 g kg−1 in the basal diet on growth rate, non-specific immune response, and disease resistance for 60 days in Oreochromis mossambicus against an opportunist pathogen, Aeromonas hydrophila. The results showed that the Shilajit enriched diets at 4.0 and 6.0 g kg−1 diets significantly (p < 0.05) enhance survival rate, weight gain (WG), protein efficiency ratio (PER), specific growth rate (SGR), and feed efficiency (FE), whereas it significantly decrease the feed conversion ratio (FCR) from weeks 1–4 when compared with control. The innate immune parameters, such as the phagocytic, complement, respiratory burst, and lysosome activities in infected fish fed with all Shilajit enriched diet were significantly (p < 0.05) enhances on weeks 2–4. A very low cumulative mortality, 8.0% and 12.0% were observed in the infected fish fed with 4.0 and 6.0 g kg−1 Shilajit enriched diets, whereas 18% mortality was found with 2 g kg−1 diet. In conclusion, 4.0 and 6.0 g kg−1 Shilajit enriched diets significantly increased the growth performance, innate immune response, and disease resistance in O. mossambicus against A. hydrophila infection.Introduction of natural mineral Shilajit in aqua-nutrition.Growth and survival of O. mossambicus were increased by Shilajit enriched diet.Shilajit enriched diet reflects significant immune response in O. mossambicus.Shilajit enriched diet shows significant disease resistance.