Background: Klebsiella pneumoniae is a major multidrug-resistant pathogen associated with severe hospital-acquired infections. Although meropenem remains a key therapeutic option, little is known about the global transcriptional response of K. pneumoniae to carbapenem exposure, especially in clinical isolates. Methods: We performed RNA-sequencing (RNA-seq) on an extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae strain exposed to meropenem at clinically relevant serum concentrations. Differentially expressed genes were identified and mapped onto central metabolic pathways. Results: Meropenem exposure triggered a profound transcriptional reprogramming. Glycolytic genes were significantly upregulated, including hexokinase, phosphoglycerate kinase, and pyruvate kinase, suggesting increased energy production via substrate-level phosphorylation. In contrast, genes in the oxidative branch of the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase and isocitrate dehydrogenase, were downregulated. Several amino acid biosynthetic pathways—including those for glutamate, serine, arginine, methionine, and branched-chain amino acids—were transcriptionally activated, indicating a shift toward anabolism and redox balance. Conclusion: Our findings reveal a coordinated metabolic adaptation in K. pneumoniae under meropenem stress, characterized by enhanced glycolysis and amino acid biosynthesis alongside partial TCA suppression. This Warburg-like phenotype may support bacterial survival, stress tolerance, and early persistence. These insights offer new perspectives on noncanonical antibiotic response pathways and potential metabolic targets for therapeutic intervention.