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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