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One of the most farmed fishes is the African catfish, Clarias gariepinus. Its production has increased by 20% annually on average during the last 20 years, but the occurrence of fish diseases, especially bacterial such as Aeromonas hydrophila infections, is hindering its activities. Also, the incorporation of plant‐derived substances in aquafeeds is limited since they frequently contain different antinutritional factors, like nonstarch polysaccharides (NSPs). However, supplementing fish diets with β‐mannanase could increase growth, antioxidants, and immunity. Despite the advantage of β‐mannanase, its effects on growth, digestive enzymes, antioxidants, and immunity in African catfish need to be elucidated. This study examined the effects of dietary β‐mannanase on the growth performance, liver enzymes, antioxidant profiles, immunity, and protection of African catfish, C. gariepinus, against A. hydrophila infection. Five isonitrogenous diets were prepared to have 400 g/kg crude protein and supplemented with β‐mannanase at 0, 1500, 3000, 4500, or 6000 thermostable endo, 1,4‐β‐mannanase units (TMUs)/kg diet and fed to 300 juveniles of the African catfish, C. gariepinus (mean weight 12.1 ± 0.1 g) for 12 weeks. Then, 10 fish from each tank received an intraperitoneal injection of 0.1 mL of A. hydrophila (5.0 × 105 CFU/mL) and observed for 14 days. Results showed dietary β‐mannanase levels considerably improved growth performance but did not affect fish survival. Also, amylase, protease, and lipase levels were significantly promoted in the fish fed with β‐mannanase‐fortified diets than the control group (p < 0.05). Enhanced gut villi and intestinal absorption areas, haematlogical profiles, and liver enzymes but reduced gut viscosity were observed in fish‐fed β‐mannanase‐fortified diets (p < 0.05). In a dose‐dependent order, including β‐mannanase in the meals of African catfish raised the levels of glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione‐S‐transferase (GST), and glutamate cysteine ligase (GCL) activities and decreased the malondialdehyde (MDA) values in African catfish (p < 0.05). Also, fish immunity was greatly (p < 0.05) enhanced due to supplementation of the diet with β‐mannanase. In addition, fish‐fed diets comprising 6000 TMU β‐mannanase/kg diet showed the lowest rates of fish mortality (7.5%) (p < 0.05). Therefore, feeding African catfish, Clarias gariepinus, β‐mannanase enhanced growth performance, increased activity of digestive enzymes, gut morphology, enhanced generation of short‐chain fatty acids, digesta potential of hydrogen (pH), and improved antioxidant profiles and immunity at the optimum dose of 5800 TMU/kg diet. Additionally, β‐mannanase protected African catfish against A. hydrophila infection. [ABSTRACT FROM AUTHOR]