The impact of Mucuna pruriens (L.) seed meal diet on growth performance, innate immune response, and disease resistance in Oreochromis mossambicus against Aeromonas hydrophila is reported for the first time. Infected O. mossambicus was fed with 2 g kg−1, 4 g kg−1, and 6 g kg−1 of M. pruriens seed meal diets significantly increased initial body weight (IBW) and final body weight (FBW) over control, for a period of 4 weeks. At 4 g kg−1 and 6 g kg−1 the enriched diet significantly (P < 0.05) enhanced the survival rate, weight gain (WG), protein efficiency ratio (PER), specific growth rate (SGR), feed conversion ratio (FCR), and feed efficiency (FE) when compared to the control; besides, from weeks 2–4 these diets significantly (P < 0.05) enhanced the complement activity, phagocytic activity, respiratory burst activity, and lysosome activity. On being fed with 4 g kg−1 and 6 g kg−1−enriched diets the cumulative mortality was lower (10% and 12%) than with 2 g kg−1 diet (24%). The present investigation suggests that the enriched diet at 4 g kg−1 and 6 g kg−1 improved the growth performance more than that of the control and negative control; it also positively enhanced the innate immunity and disease resistance against A. hydrophilla in O. mossambicus. Hence M. pruriens can be used as a feed additive to stimulate immunity for effective production of economically valuable freshwater fish, O. mossambicus.