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A feeding trial was conducted to determine the amount of soybean meal (SBM) that could replace fish meal (FM) without compromising growth and health of Asian red‐tailed catfish (Hemibagrus wyckioides). Five isonitrogenous and isoenergetic diets (S0, S15, S30, S45 and S60) were formulated with SBM to replace 0%, 15%, 30%, 45% and 60% of FM. The replacement level up to 30% improved daily growth coefficient, plasma adenosine monophosphate deaminase (AMPD) and alanine aminotransferase (ALT) activities and IgM content, and hepatic ALT, aspartate aminotransferase (AST) and glutathione reductase activities, whereas these were depressed by a further inclusion. The highest protein efficiency ratio and lowest feed conversion ratio were observed in fish fed the S15 diet. Replacement of FM with SBM generally decreased plasma insulin and insulin‐like growth factor 1 (IGF‐1) contents and hepatic catalase activity, whereas no significant differences were observed among fish fed the S0, S15 and S30 diets. In contrast, replacing FM with SBM generally increased blood urea nitrogen content, and that was higher in fish fed the S60 diet compared to fish fed the S0 diet. The highest growth hormone (GH) and glutamate dehydrogenase (GDH) activities were observed in fish fed the S30 diet. Fish fed the S30 and S45 diets exhibited the highest hepatic AMPD, GDH, IGF‐1 and target of rapamycin mRNA levels and muscle AMPD and GDH mRNA levels, whereas those were lowest in fish fed the S60 diet. These results indicate that under the reported conditions SBM may be included in the diet up to 222 g/kg as a substitute for FM, replacing about 30% of FM protein in juvenile H. wyckioides.