Fluoroquinolone-resistant Pseudomonas aeruginosa poses a significant global health concern, particularly in healthcare settings. This opportunistic pathogen has developed resistance against multiple classes of antibiotics, rendering infections challenging to treat. The present study focused on identifying quinoline analogs as potential inhibitors of gyrA in fluoroquinolone-resistant P. aeruginosa. Utilizing structural bioinformatics, molecular docking, molecular dynamics (MD) simulations, and MM/PBSA binding energy analyses, the quinoline analog, N-benzylquinoline-8-sulfonamide (M2), emerged as the most promising candidate. Molecular docking revealed M2's better binding affinity to gyrA wild type as well as frequently observed mutants, demonstrated average binding energy of - 8.14 kcal/mol, significantly better than ciprofloxacin (- 7.13 kcal/mol) and levofloxacin (- 6.57 kcal/mol). M2 exhibited a robust inhibition constant of 1.09 µM, surpassing control antibiotics ciprofloxacin (6.11 µM) and levofloxacin (15.34 µM). MD simulations validated the dynamic stability of M2 and gyrA complexes (wild-type and mutant), whereas MM/PBSA analysis confirmed strong binding energetics. Principal Component Analysis (PCA) further validated the stability of these complexes by identifying the global energy minima across conformational landscapes. M2 exhibited enhanced efficacy and stability against resistance-associated mutations compared to the standard antibiotics ciprofloxacin and levofloxacin. These findings underscore M2's potential as a potent therapeutic agent against fluoroquinolone-resistant P. aeruginosa. Further experimental validation is necessary to confirm its efficacy and to translate these computational insights into clinical applications.