The urge to develop a novel, environmentally friendly antimicrobial is growing, particularly in view of the increasing pathogens’ resistance to the current therapies. Thus, this study represents the first initiative to address the antibacterial characteristics of naringenin (NAR; 17.50 mg/L) as a water additive flavanone dissolved in dimethyl sulfoxide (DMSO) to support the resistance of Nile tilapia (Oreochromis niloticus) against Proteus mirabilis (bacterial infection). For 15 days, a total of 250 fish (24.30 ± 1.12 g) were split into five groups [control, DMSO, NAR, P. mirabilis, and NAR+P. mirabilis]. Findings showed that P. mirabilis triggered a renal-hepatic dysfunction, as evidenced by a significant increase in creatinine, alanine aminotransferase, and aspartate aminotransferase levels (P < 0.001), and increased fish mortality (40.00 %). Oxidative damage and stress response were induced by P. mirabilis challenge, where a noteworthy rise in the malondialdehyde, cortisol, and glucose concentrations, and a drop in glutathione peroxidase and catalase activities were noted (P < 0.001). A substantial decrease in the neurotransmitter (serotonin and dopamine) concentrations was observed in the P. mirabilis group (P < 0.001). The histopathological shifts in the gills (distorted most gill filaments), kidney (necrotic changes within renal tubules and atrophic glomerular tuft), liver (fatty degeneration and congested portal vein), and brain (pyknotic neurons and hyperplasia of glia cells) were the outcome of P. mirabilis infection. Intriguingly, NAR water treatment reversed all the negative effects of P. mirabilis infection and decreased fish mortality (14.00 %). In addition, NAR lowered bacterial load in the tissues (gills, kidney, liver, and brain) of the P. mirabilis-infected fish. By emphasizing NAR’s ability to enhance the physiological and antioxidant status of Nile tilapia challenged with P. mirabilis, this trial highlights the essential significance of NAR as an exceptional anti-bacterial to sustain the aquaculture industry.