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<i>Pseudomonas aeruginosa</i> causes chronic infections, such as cystic fibrosis, endocarditis, bacteremia, and sepsis, which are life-threatening and difficult to treat. The lack of antibiotic response in <i>P. aeruginosa</i> is due to adaptive resistance mechanism, which prevents the entry of antibiotics into the cytosol of the cell to achieve tolerance. Among the different groups of antibiotics, aminoglycosides are used as a parenteral antibiotic for the treatment of <i>P. aeruginosa</i>. This study aimed to determine the kinetics of antibiotic tolerance and gene expression changes in <i>P. aeruginosa</i> exposed to amikacin, gentamicin, and tobramycin. These antibiotics were exposed to <i>P. aeruginosa</i> at their MICs and the experimental setup was monitored for 72 h, followed by the measurement of optical density every 12 h. The growth of <i>P. aeruginosa</i> in the MICs of antibiotics represented the kinetics of antibiotic tolerance in amikacin, gentamicin, and tobramycin. The transcriptomic profile of antibiotic exposed <i>P. aeruginosa</i> PA14 was taken from the Gene Expression Omnibus (GEO), NCBI as microarray datasets. The gene expressions of two datasets were compared by test versus control. Tobramycin-exposed <i>P. aeruginosa</i> failed to develop tolerance in MICs of 0.5 µg/mL, 1 µg/mL, and 1.5 µg/mL, whereas amikacin- and gentamicin-treated <i>P. aeruginosa</i> developed tolerance. This illustrated the superior in vitro response of tobramycin over gentamicin and amikacin. Further, in silico transcriptomic analysis of tobramycin-treated <i>P. aeruginosa</i> resulted in differentially expressed genes (DEGs), enriched in 16s rRNA methyltransferase E, B, and L, alginate biosynthesis genes, and several proteins of the type II secretion system (T2SS) and type III secretion system (T3SS). The regulation of <i>mucA</i> in alginate biosynthesis, and <i>gidB</i> in RNA methyltransferases, suggested an increased antibiotic response and a low probability of developing resistance during tobramycin treatment. The use of tobramycin as a parenteral antibiotic with its synergistic combination might combat <i>P. aeruginosa</i> with increased response.