The current trial investigates the impacts of replacing fish meal (FM) with corn gluten meal (CGM) on tilapia fish's productive performance and economic efficacy. A 12-week feeding experiment was conducted to examine the impact of substituting FM with CGM on 360 fingerlings of Nile tilapia (with initial weight = 3.01 ± 0.01 g). The experimental fish were randomly divided into six equal groups, with triplicates in each group (20 fish per replicate). The control group was administered FM-based diets (CGM0) with 20% FM. Whereas, CGM was employed to substitute 20%, 40%, 60%, 80%, and 100% of dietary FM protein in the other five isonitrogenous (crude protein: 32.85%) and isoenergetic (17.60 MJ kg-1 dry matter) formulated diets. Meanwhile, the findings showed a significant (p<0.05) decrease in performance markers (final biomass, weight gain and weight gain percent) for the group that received a high replacement amount of FM with CGM (80 or 100%) compared to control and other treated groups. Compared to the control group, substituting FM with 20, 40%, or 60% CGM significantly (p<0.001) increased protein efficiency measures. Furthermore, specific growth rate, feed conversion rate, feed efficiency, and survival rate reported no significant effect at any replacement level. Meanwhile, incorporating CGM in tilapia fish diets as an alternative to fish meals with high levels (80-100%) significantly increased serum levels from protein constituents, thyroid agents, and triglyceride content. Moreover, the replacement of FM with CGM is more economical. In conclusion, incorporating CGM instead of FM up to the level of 60% does not negatively impact the fish performance, but also improves the economic efficiency of Nile tilapia feed.