<jats:title>Abstract</jats:title><jats:p><jats:italic>Klebsiella pneumoniae</jats:italic> is an opportunistic pathogen causing nosocomial and community-acquired infections. <jats:italic>Klebsiella</jats:italic> has developed resistance against antimicrobials including the last resort class; carbapenem. Currently, treatment options for carbapenem-resistant-<jats:italic>Klebsiella</jats:italic> (CRK) are very limited. This study aims to restore carbapenem effectiveness against CRK using celastrol and thymol. Clinical <jats:italic>Klebsiella</jats:italic> isolates were identified using biochemical and molecular methods. Antimicrobial susceptibility was determined using disk-diffusion method. Carbapenemase-production was tested phenotypically and genotypically. Celastrol and thymol-MICs were determined and the carbapenemase-inhibitory effect of sub-MICs was investigated. Among 85 clinical <jats:italic>Klebsiella</jats:italic> isolates, 72 were multi-drug-resistant and 43 were meropenem-resistant. Phenotypically, 39 isolates were carbapenemase-producer. Genotypically, <jats:italic>bla</jats:italic><jats:sub>NDM1</jats:sub> was detected in 35 isolates, <jats:italic>bla</jats:italic><jats:sub>VIM</jats:sub> in 17 isolates, <jats:italic>bla</jats:italic><jats:sub>OXA</jats:sub> in 18 isolates, and <jats:italic>bla</jats:italic><jats:sub>KPC</jats:sub> was detected only in 6 isolates. Celastrol showed significant inhibitory effect against carbapenemase-hydrolytic activity. Meropenem-MIC did not decrease in presence of celastrol, only 2-fold decrease was observed with thymol, while 4–64 fold decrease was observed when meropenem was combined with both celastrol and thymol. Furthermore, thymol increased CRK cell wall-permeability. Molecular docking revealed that celastrol is superior to thymol for binding to KPC and VIM-carbapenemase. Our study showed that celastrol is a promising inhibitor of multiple carbapenemases. While meropenem-MIC were not affected by celastrol alone and decreased by only 2-folds with thymol, it decreased by 4–64 folds in presence of both celastrol and thymol. Thymol increases the permeability of CRK-envelope to celastrol. The triple combination (meropenem/celastrol/thymol) could be useful for developing more safe and effective analogues to restore the activity of meropenem and other β-lactams.</jats:p>