This study investigated the occurrence and antimicrobial susceptibility of Pseudomonas aeruginosa in Oreochromis niloticus and evaluated the antibacterial effect of essential oils (Mintodin®) in vitro and in vivo. A total of 100 samples of apparent health Oreochromis niloticus collected from fish markets and examined bacteriologically for Pseudomonas aeruginosa which isolated from24/100 (24%) of the samples tested and confirmed via PCR, yielding a 956 bp product specific to 16S rDNA gene. Antibiotic susceptibility testing showed high resistance rates, with 95.8% resistant to amoxicillin and 87.5% to erythromycin. Moreover, 83.33% of isolates were multidrug-resistant (MDR), and 16.66% exhibited extensive drug resistance (XDR).An experimental infection study was conducted on apparently healthy 150 Nile tilapia were divided into five groups: G1 (healthy control), G2 (infected, untreated control), G3 (infected , doxycycline-treated), G4 (infected, essential oil treated), G5 (pretreated with essential oil, then infected and doxycycline-treated). The infected untreated group (G2) showed significant reductions in RBC count, Hb, PCV, lymphocytes, and monocytes, alongside increased serum ALT, AST, urea, creatinine, and glucose, with decreased antioxidant enzyme activity (catalase, GSH-Px). In post mortem examination, sign^s of septicemia were observed and histopathological changes of different organs of infected fishes were described.  However, treatment with doxycycline (G3), essential oils (G4), or a combination of pre-treatment with essential oils followed by doxycycline/e (G5) resulted in notable improvements in blood parameters, oxidative stress markers, inflammatory responses, and histopathological alterations. Notably, G5 showed the most promising results, with upregulated antioxidant genes expression (SOD, CAT) and metabolic gene expression (Tfam), while downregulating the pro-inflammatory cytokine IL-6. These findings suggest that essential oils could enhance the therapeutic efficacy of antibiotics and serve as a protective strategy against P. aeruginosa infections in aquaculture.