Aquaculture of the African catfish Clarias gariepinus has rapidly increased in South-East Asia over recent years, which has now become one of the most cultivated species. This culture intensification has resulted in the development of various diseases, among which the Motile Aeromonas Septicaemia (MAS) caused by Aeromonas hydrophila. The present study aimed at investigating the potential of three plants, Piper betle, Psidium guajava, and Tithonia diversifolia, to prevent this disease using an enriched fish diet during 4 weeks. Though the minimum inhibitory and bactericidal concentrations of acetone–extracts were relatively high (2–32 mg mL-1 and 8–64 mg mL-1, respectively), all three plant powders imbedded in feed significantly reduced fish mortalities following an experimental infection with A. hydrophila, as indicated by relative percent survivals (RPS) ranging from 77 to 79%. When used in combination, the three plant extracts showed no interaction in vitro. Even though they improved RPS in comparison with controls, they were, however, less efficient in reducing mortalities than single plants. None of the plant-enriched diet had a clear effect on blood cell count or on reactive oxygen species (ROS) production (except for P. betle, which significantly increased ROS production after infection); however, both individual plants and their combinations significantly limited the drop of hematocrit following infection. Altogether, these results indicate that selection of plants for herbal therapy is complex and might depend on several in vivo criteria, and as such should not solely rely upon measurement of their antimicrobial activity.