The effect of diet supplemented with Shilajit, a multi-component natural mineral substance on the antioxidant activity, immune response, and disease resistance in freshwater prawn, Macrobrachium rosenbergii (de Man) against Aeromonas hydrophila is reported. The total hemocyte count (THC) and phagocytic activity significantly increased with 2 g kg−1 supplemented diet on first week and with other enriched diets on weeks 2 and 4. The respiratory burst (RB) activity and glutathione peroxidase (GPx) activity were significantly increased with 2 g kg−1 supplemented diet on weeks 1 and 2 whereas 2 and 4 g kg−1 diets on week 4. The phenoloxidase (PO) activity increased significantly with 2 g kg−1 diet only on second week and with other enriched diets only on fourth week. The superoxide dismutase (SOD) activity increased significantly with any enriched diet during the experimental period except with 6 g kg−1 diets on first week. However, the glutathione reductase (GR) activity was enhanced significantly only with 2 g kg−1 enriched diets on weeks 2 and 4. The cumulative mortality of the prawn fed with 2 and 4 g kg−1 enriched diets was 10% and 15% whereas with 6 g kg−1 diet the mortality was 20%. The results suggest that diet enriched with Shilajit at 2 g kg−1 or 4 g kg−1 positively enhances the antioxidant activity, immunity, and disease resistance in M. rosenbergii against A. hydrophila.