The impact of Cucurbita mixta (L.) seed meal enriched diet on growth performance, innate immune response, and disease resistance in Oreochromis mossambicus against Aeromonas hydrophila was investigated. O. mossambicus was fed with 2 g kg−1, 4 g kg−1, and 6 g kg−1C. mixta seed meal diets for a period of 4 weeks. The results indicated that C. mixta seed meal diets at 4 g kg−1 and 6 g kg−1 significantly (P < 0.05) enhances the survival rate, weight gain (WG), protein efficiency ratio (PER), specific growth rate (SGR), feed conversion ratio (FCR), and feed efficiency (FE) from weeks 1–4 when compared to control. C. mixta seed meals administered as feed supplements significantly (P < 0.05) enhanced the complement activity, phagocytic activity, respiratory burst activity, and lysosome activity in infected fish fed with 4 g kg−1 and 6 g kg−1 of C. mixta seed meal enriched diet from weeks 2–4. The cumulative mortality was lower in the fish fed with 4 g kg−1 and 6 g kg−1 of C. mixta seed meal enriched diets (15% and 18%) than with 2 g kg−1 diet (26%). The present investigation suggested that C. mixta seed meal enriched diet at 4 g kg−1 and 6 g kg−1 enhance the better growth performance, innate immunity, and disease resistance against A. hydrophilla in O. mossambicus.