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) as aqueous additive in comparison to cephalexin (CE) antibiotic in Nile tilapia (Oreochromis niloticus); experimentally challenged with Proteus mirabilis (PM). Nile tilapia (N = 240) were allocated into eight groups, each group had 3 replicates. 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-1, respectively. Meanwhile, the fourth group (CE) was exposed to CE at 500 mg L-1. The fifth group (PM); served as control positive (challenged with P. mirabilis (5×106 CFU mL-1) 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 in the immunological response (lysozyme and nitric oxide) and antioxidant (catalase, superoxide dismutase, reduced glutathione content) biomarkers were noted in the PM group. Surprisingly, considerable improvements in all these indices with reduction in the mortality was noticed in CP- and CE-treated and infected groups. Thus, we recommend the usage of CP (0.02 g L-1) as a natural, potent immuno-stimulant and antibacterial agent alternative to antibiotic to avoid their negative impacts and pave the way towards a sustainable aquaculture industry.