Currently, herbal therapy has become an important alternative that is widely used in aquaculture to limit the use of antibiotics and other chemicals during fish production cycle. Correspondingly, the ongoing study was performed to evaluate the therapeutic efficacy of clove powder (CP) (Syzygium aromaticum, L.) as an aqueous additive in comparison to cephalexin (CE) antibiotic in Nile tilapia (Oreochromis niloticus, L.) experimentally challenged with Proteus mirabilis (PM). Nile tilapia (N = 240) were allocated into eight groups, each group had three replicates. The first group (control) was neither challenged, nor treated. Fish of the second and third groups (CP1 and CP2) were maintained in water containing CP at 0.01 and 0.02 g/L, respectively .Meanwhile, the fourth group (CE) was exposed to CE at a concentration of 0.5 g/L. The fifth group (PM) served as a positive control (challenged with P. mirabilis (5×106 CFU/mL) and non-treated). Meanwhile, the other three groups (CP1-PM, CP2-PM, and CE-PM) were intraperitoneally challenged with P. mirabilis, then treated with medical bath containing either CP or CE with the same concentrations as previously mentioned. The experiment lasted for 15 days, during which all fish were kept under observation. Following the challenge by P. mirabilis, the highest mortality rate (85%), notable clinical symptoms, elevated stress (glucose and cortisol) and hepato-renal function (alanine and amino transferases, urea, and creatinine) indicators were observed. Marked decline (P< 0.05) in the immunological response (lysozyme and nitric oxide) and antioxidant biomarkers (catalase, superoxide dismutase, and reduced glutathione content) were noted in the PM group. Surprisingly, a considerable improvement in all these indices with reduction in the mortality was noticed in P. mirabilis-challenged groups that treated with either CP2or CE (30% and 20% respectively).Thus, we recommend the usage of CP (0.02 g/L) as a natural, potent immuno-stimulant, and antibacterial agent alternative to antibiotics to avoid their negative impacts and pave the way towards a sustainable aquaculture industry.