Medicinal herbal feed that used as feed additives are widely applied in livestock production and may be applicable to aquaculture production systems. The present study explores the modulatory effects of incorporation of herbal combination of black cumin seeds (Nigella sativa), peppermint (Mentha piperita) and fennel (Foeniculum vulgare), on African Sharptooth Catfish, Clarias gariepinus. For this purpose, a total of 72 catfish were randomly distributed into 6 groups of 12 fish each and fed on the experimental diets for 45 successive days. Fish of first group were fed on basic diet only while, those of the second one were fed on basic diet supplemented with 0.5% from each medicinal plant while, other 4 groups were subjected to challenge experiment byinjection with Vibrio vulnificus. The third group was kept non-injected, fourth group was injected by saline, fifth and sixth groups were injected by Vibrio vulnificus after feeding with basic diet and basic diet with herbs, respectively. Results proved that, total antioxidant capacity, serum total proteins, albumins and globulins were observed to be significantly higher in the treated group as compared to the control. Lymphocytes percent increased significantly in herbal fed group comparing to the control group while, neutrophils percent decreased significantly. Although serum urea level was not affected by herbal supplement, serum creatinine level was decreased significantly. Body weight gain of C. gariepinus increased significantly after herbal administration. Catfish challenged with a Vibrio vulnificus isolate and received the herbal diet showed less mortality than the control group. Fish fed on the herbal diet exhibited normal histological structure of liver, kidney and spleen. In conclusion, based on the current results together with the low cost and the potential antioxidant and immune effects of mixed herbal medicinal plants used in the study, it is recommended to be used in fish feed to diminish the mortalities caused by some aquatic pathogens.