The study investigated the dietary effects of medicinal herbs extract and multiple probiotics mixture on the growth performance, innate immune response and antibacterial activity of nile tilapia Oreochromis niloticus. Tilapia were divided in four groups. The first is a fish group fed a basal diet added with 40% medicinal herbs extract (MHE). The second is a fish group fed a basal diet supplied with 2×10⁸ CFU/g of 2 Bacillus sp, 2 Lactobacillus sp and 2 Yeast sp, respectively (PB). The third group was fed with a mixture of probiotics (2 Bacillus sp, 2 Lactobacillus sp and 2 Yeast sp) with the medicinal herbs extract added in basal diet (MHE+PB). The fourth group was fed only a basal diet (C). In a non-specific immune parameters analysis, respiratory burst activity, lysozyme activity, phagocytic activity (PA), alternative complement pathway activity (ACH₅₀) and superoxide dismutase (SOD) activity were significantly (p<0.05) increased in the group MHE+PB compared to other groups. Both PB and MHE groups showed a significant (p<0.05) increase in respiratory burst activity, lysozyme activity compared to the control C group, whereas no significant differences were observed in PA, ACH₅₀ and SOD activity compared to the control group. In challenging test, fish were administered with Edwardsiella tarda (E. tarda) on 30 days after feeding with each experimental diet and viable E. tarda cell reduction was checked over 21 days post injection. MHE+PB group showed a significantly (p< 0.05) reduced E. tarda cells compared to other groups. No significant antibacterial difference (p >0.05) was observed between PB and MHE only treated group. Compared to the control, a significant antibacterial difference (p< 0.05) appeared in PB but not in MHE (p >0.05). The results suggest that the probiotics and MHE mixture could be utilized as an alternative to antibiotics in the control of fish diseases caused by E. tarda.