Zinc (Zn) is an important trace element in fish diets that is required for growth, immunity and antioxidant defense mechanisms. The current study assessed the effects of both organic and nanoparticle zinc oxide (i.e. ZnO and ZnO-NPs) on growth performance, immune response and the antimicrobial effect against Pseudomonas aeruginosa in African catfish (Clarias gariepinus). Fish were fed either a control diet, or diets supplemented with organic ZnO at concentrations of 20 and 30 mg/Kg or ZnO-NPs at concentrations of 20 and 30 mg/Kg. After 60 days, a subsample of the fish was injected intraperitoneally with 3x107 CFU/mL of P. aeruginosa. Results showed that body weight gain, feed conversion ratio and specific growth rates were significantly increased in ZnO-NPs20 compared to all other groups. The dietary supplementation with 20mg/Kg of ZnO-NPs improved the antioxidant status of fish. Moreover, IgM, lysozyme and nitric oxide showed a significant increase in the fish which received the ZnO-NPs20 supplemented diet. A significant up-regulation of growth and stress related genes was seen in the ZnO-NPs20 supplemented group compared to other groups. However, there was no significant difference in the immune-related genes expression among ZnO-NPs20, ZnO-NPs30 and ZnO-30 groups. These findings highlight the potential use of nano-ZnO for improving growth performance, antioxidant status, immunological status and antibacterial activity against P. aeruginosa in African Catfish.