In a feeding experiment, cottonseed meal (CSM) was used to replace fishmeal (FM) in the diet of snubnose pompano supplemented with lysine and methionine to assess the growth, nutritive profile, hematological, histological and stress biomarkers response. Experimental fishes were randomly stocked in five treatments each with triplicates. Five isonitrogenous and isolipidic diets with graded level of CSM (0, 8.7, 17.4, 26.0 and 34.7%) as replacement for FM protein (0, 25, 50, 75, and 100%) were formulated and fed to respective treatments. Comparison between various parameters among the treatments was made using orthogonal polynomial contrasts to indicate the statistical significance. Higher alkaline phosphatase, acid phosphatase, lactate dehydrogenase, malate dehydrogenase, aspartate and alanine aminotransferase activities were observed in 0CSM group and followed by 100CSM group as higher inclusion level of CSM with higher free gossypol content did not affect the metabolic enzyme activities. The maximum muscular free gossypol accretion of 1.28 mg kg-1 (on wet basis) was recorded in 100CSM group which was very well below the critical limit set by FDA. As a conclusion, fishmeal can be completely replaced using cottonseed meal in the diet of pompano without adverse effect on growth, metabolism and general health.