A feeding trial for 70 days was designated on Nile tilapia, Oreochromis niloticus (O. niloticus). A total of 200 fish (34.38 ± 0.05 g) were assigned into five groups, four replicates for each (10 fish/replicate; 40 fish/group) and received five isonitrogenous and isocaloric diets with five replacement levels of fishmeal (FM) with kidney bean (Phaseolus vulgaris L) protein hydrolysate (KBH) (0, 25, 50, 75, 100%). The findings demonstrated a significant increase in the performance metrics (final body weight, total weight gain, average daily weight gain, protein efficiency ratio, and specific growth rate) with a considerable improvement in the feed conversion ratio across all replacement levels, with the greatest value obtained in the KBH75 and KBH100 groups. Regarding the broken line regression analysis, the optimum FM replacement level with KBH was 76%. By replacing FM with KBH, the growth hormone and digestive enzymes (amylase and protease) levels were significantly increased, whilst the glucose and leptin hormone levels significantly declined. The amino acid transporters (solute carrier family 15 member 2 and solute carrier family 26 member 6), insulin growth factor-1, the immune-associated genes (interleukin- 8, toll-like receptors-7, and cc-chemokine), and the antioxidant-associated genes (glutathione peroxidase, superoxide dismutase, and Glutathione synthetase) expression was substantially boosted in all replacement levels, where the KBH50 group recorded the highest expression. As well as the mRNA expression of myostatin was downturned in all replacement levels relative to the KBH0 group. Improving the immune functions (lysozyme, complement 3, nitric oxide, phagocytic %, and phagocytic index) was noticed by FM replacement with KBH. The cumulative mortality as a result of challenging with Aeromonas sobria at the end of the feeding trial was decreased by increasing the replacement level (80, 40, 37, 30, and 25% for KBH0, KBH25, KBH50, KBH75, and KBH100, respectively). From the economic point of view, the feed costs and feed cost/ kg gain declined in the KBH75 and KBH100 diets. From the aforementioned outcomes, KBH could replace the FM up to 100% with improving the growth and their related genes expression, digestive enzymes activity, and immune/antioxidant parameters and their encoding gene expression, and the optimal replacement level was 76%. The replacement of FM with KBH was economically efficient.