The impact of partial replacement of fish meal with methylated soy protein isolates (MSPI) on fish performance was assessed in 10 weeks feeding trial using Nile tilapia,Oreochromisniloticusfingerlings (n = 225) with average initial weight 18.51 ± 0.05 g/fish. The effects on the growth, histopathological condition of certain organs, economic efficiency, immune status, and disease resistance to Aeromonashydrophila were evaluated. The fingerlings were randomly segregated into five experimental groups with varying percentages of fish meal with substituted MSPI: 0%, 22%, 44%, 66%, and 88% (MSPI0, MSPI22, MSPI44, MSPI66, and MSPI88). The results of final body weight, body weight gain, daily body weight gain, protein efficiency ratio,and SGR were uniquely increased by the treatment MSP22, while increasing the level of MSPI more than 22% resulted in linearly proportional decreases inthese parameters over the respective control. The broken-line regression analysis using feed conversion ratio and body weight gain data revealed that the maximum dietary replacement of fishmeal with MSPI was 66%. Alterations in the histomorphological structures of the liver and intestine were observed with an increased level of replacement.The total weight of surviving fish, phagocytic index, IgM level, and lysozyme activity post bacterial challenge were significantly increased by MSPI substitution in fish meal. The survival percentage after the bacterial challenge was increased by MSPI inclusion, the highest survival percentage was recorded in the MSPI66 group (95.55%) compared to MSPI0 (66.66%).MSPI22 increased the total return, net profit, and performance index %. It could be concluded that the maximum dietary replacement of fishmeal with MSPI Oreochromis niloticus fingerlings was 66%. The growth performance was decreased by increasing the substitution percentage of fish meal by MSPI. MSPI was shown to be a good immune-modulating substance and improved gut health. MSPI substitution at 88% is not recommended due to the bad effect on the hepatic and intestinal tissues.