A ten-week feeding trial was carried out to investigate the effects of replacing fishmeal (FM) with soybean meal (SBM) and brewer's yeast (BY) on growth performance, blood parameters, oxidative stress and micromorphology of liver and intestines in brown bullhead (Ameiurus nebulosus L.). Fish were fed nine feeds in which FM was replaced with 25%, 50%, 75% and 100% SBM (K1, K2, K3 and K4) and 17% + 8%, 42% + 8%, 67% + 8% and 92% + 8% of SBM/BY combination (K5, K6, K7, K8). Growth indices showed greater outcomes for the K2 group in comparison to all other groups. A decrease in plasma cholesterol and triglycerides concentrations was found after FM replacement. Activity of SOD was higher in groups K4, K7 and K8. The early inflammatory indications with abnormal vacuolization of lamina propria and basal epithelium were present in diets K4 and K8. Hepatocytes were irregular in shape with signs of inflammatory reaction in diet K8. A decreased perimeter of hepatocyte nuclei was detected in all experimental diets when compared with the control. This study demonstrates that the optimal replacement of FM with SBM/BY in brown bullhead diets contains up to 50% of FM replaced with SBM in order to obtain advantageous growth performance and adequate health condition.