The present study evaluated the effects of partially substituting fish meal (FM) with poultry by-product meal (PBPM) on the growth, muscle composition, and tissue biochemical parameters of coho salmon (Oncorhynchus kisutch) post-smolts. Five isonitrogenous (7.45% nitrogen) and isoenergetic (18.61 MJ/kg gross energy) experimental diets were made by substituting 0%, 10%, 20%, 40%, and 60% FM protein with PBPM protein, which were designated accordingly as PBPM0 (the control), PBPM10, PBPM20, PBPM40, and PBPM60, respectively. Each diet was fed to triplicates of ten post-smolts (initial individual body weight, 180.13 ± 1.32 g) in three floating cages three times daily (6:50, 11:50, and 16:50) to apparent satiation for 84 days. Both specific growth rate (SGR) and protein efficiency ratio did not differ significantly (p > 0.05) among the control, PBPM10, and PBPM20 groups, which were remarkably (p < 0.05) higher than those of the PBPM40 and PBPM60 groups. Feed conversion ratio varied inversely with SGR. The PBPM replacement had no remarkable effects on the morphological indices and proximal muscle components. The control and PBPM10 groups led to significantly higher muscle contents of leucine, lysine, and methionine than groups of higher PBPM inclusion. The groups of PBPM40 and PBPM60 obtained significantly (p < 0.05) higher serum alanine aminotransferase and aspartate aminotransferase activities than the control and low PBPM inclusion groups. The control group had significantly higher albumin and total cholesterol contents than the groups with PBPM inclusion. The control group had significantly higher triglycerides content than the PBPM60 group. The PBPM60 group had significantly lower contents of high-density lipoprotein, low-density lipoprotein, and total protein than the control and PBPM10 groups. The high PBPM replacement level up to 40% and 60% had adverse effects on hepatic malondialdehyde levels. The catalase and superoxide dismutase activities were not affected by low PBPM inclusion, but significantly decreased in high-PBPM-inclusion groups. Based on broken-line regression analysis of SGR and PER, the optimum dietary PBPM replacing level was evaluated to be 16.63–17.50% of FM protein for coho salmon post-smolts.