The effect of substituting fish meal (FM) by tuna by-product meal (TBM) on growth and feed availability of red sea bream (Pagrus major) was investigated. Six experimental diets were crested to be isonitrogenous (51.5%) and isolipidic (14.5%). The control (Con) diet contained 55% FM. FM substitution in the Con diet was made in increments of 20 percentage points (20, 40, 60, 80, and 100%), named as the TBM20, TBM40, TBM60, TBM80, and TBM100 diets, respectively. Juvenile red sea bream were stocked into 18, 300 L flow-through tanks (50 fish/tank). Red sea bream were hand-fed with each diet until satiation for 8 weeks. No statistical differences in weight gain, specific growth rate (SGR), and feed consumption were found among red sea bream fed the Con, TBM20, and TBM40 diets. Furthermore, feed utilization of fish fed the TBM20, TBM40, TBM60, and TBM80 diets was comparable to red sea bream fed the Con diet. The biological indices, biochemical composition, and hematological parameters of fish were not statistically altered by dietary FM replacement with TBM. The greatest economic profit index was achieved in the TBM40 diet. In conclusion, the replacement of 40% FM with TBM in red sea bream diet appears to be the most recommendable approach without producing retarded growth and feed availability, but maximizing EPI to farmers.