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To determine the impact of replacing fish meal (FM) in the diet with various levels of soybean meal (SBM) on the spotted knifejaw Oplegnathus punctatus, a 56 day feeding trial was done. Seven diets were formulated with SBM to replace 0% (SBM0), 30% (SBM30), 40% (SBM40), 50% (SBM50), 60% (SBM60), and 70% (SBM70) of FM protein, and SBM50 + T was developed on the basis of SBM50 with the addition of 1.2% taurine. There were triplicate groups of 18 fish (initial weight: 14.62 ± 0.02 g). The weight gain (WG), specific growth rate (SGR), feed efficiency (FE), and protein efficiency ratio (PER) values of the SBM0, SBM30, and SBM50 + T groups were found to be significantly higher than those of the SBM60 and SBM70 groups (p < 0.05). The daily energy gain (DEG), daily nitrogen gain (DNG), daily lipid gain (DLG), energy retention (ER), nitrogen retention (NR), and lipid retention (LR) values decreased significantly with increasing dietary SBM levels (p < 0.05). The highest retention of most amino acids (except lysine) was observed in the SBM30 group (p < 0.05). The lipid content of the whole body and dorsal muscle decreased significantly as dietary SBM levels increased (p < 0.05). Fish fed the SBM70 diet had the lowest serum triglyceride (TG) concentrations (p < 0.05). The effects of different treatments on total cholesterol (T-CHO) were not significant (p > 0.05). Fish fed the SBM0 and SBM30 diets had the highest amylase (AMS) and lipase (LPS) activities (p < 0.05). The lowest liver superoxide dismutase (SOD) and catalase (CAT) activities were observed in the SBM70 group. The malondialdehyde (MDA) concentration of the SBM50 to SBM70 groups were significantly higher than that of other groups (p < 0.05). The levels of interleukin 8 (il-8) mRNA were highest in fish fed the SBM0, SBM30, and SBM50 + T diets (p < 0.05), while the level of transforming growth factor β1 (tgf-β1) was the opposite (p < 0.05). According to the broken line regression of WG and FE, the highest level of FM substitution by SBM for Oplegnathus punctatus was 24.07–25.31%.