Pseudomonas aeruginosa causes a variety of hospital-acquired infections and develops resistance to diverse classes of antibiotics. Recently, combination therapy has become an attractive strategy to reduce the emergence of antibiotic resistance in bacteria, particularly in P. aeruginosa. Combinations of aminoglycosides and β-lactam/carbapenem antibiotics have been explored for their efficacy against Pseudomonas aeruginosa. However, the synergistic effects and the potential for antibiotic resistance development with specific combinations of these two classes remain unassessed in the context of long-term usage. In this study, the synergistic activity of amikacin and imipenem combination on P. aeruginosa was evaluated based on Fractional Inhibitory Concentration (FIC) values using a checkerboard assay. Then, the serial exposure of P. aeruginosa to sub-MIC values of each antibiotic or of their combination was performed to assess the antibiotic resistance development over a 14-day period. Moreover, the antimicrobial susceptibility profile was analyzed to evaluate the susceptibility of the antibiotic-exposed P. aeruginosa. As a result, the checkerboard assay showed a synergistic effect between amikacin and imipenem (FICI ≤ 0.5 µg/mL). Besides, when being exposed to sub-MIC values of amikacin P. aeruginosa significantly developed 256 folds after 14 days, from 0.5 µg/mL to 128 µg/mL. On the other hand, when being exposed to imipenem, MIC of imipenem increased by only 16 folds, from 8 µg/mL to 128 µg/mL. The combination result did not provide a preventive effect on resistance development. The antibiotic-exposed bacteria obtained after 14 days of serial exposure only developed resistance to an aminoglycoside (gentamicin), and a cephalosporin (ceftazidime) but not to other antibiotics. To summarize, the combination of imipenem and amikacin showed synergistic effects but did not have a prevention effect on the antibiotic resistance development.