Background Neonatal sepsis caused by Klebsiella pneumoniae remains a major contributor to morbidity and mortality worldwide, particularly in neonatal intensive care units (NICUs). The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) has substantially limited therapeutic options. Although meropenem is widely used for severe Gram-negative infections, clinical responses have occasionally been observed in neonates despite documented in vitro resistance. This phenomenon suggests a clinically significant discordance between antimicrobial susceptibility testing and therapeutic outcomes.Methods A narrative literature review was conducted to evaluate clinical responses to meropenem in neonates with infections caused by meropenem-resistant Klebsiella pneumoniae. Electronic databases including PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library were searched for studies published between 1990 and 2025. Eligible studies included neonates aged 0–28 days with confirmed K. pneumoniae infection treated with meropenem and reporting both antimicrobial susceptibility data and clinical outcomes. Following screening of 180 records and removal of duplicates, 13 studies comprising retrospective cohorts, case series, and case reports were included. Findings were synthesized narratively due to heterogeneity in study design and reported outcomes.Results Meropenem monotherapy demonstrated limited and inconsistent effectiveness against CRKP infections in neonates, particularly in cases involving carbapenemase-producing strains such as NDM. However, partial clinical responses were occasionally observed despite in vitro resistance. Improved outcomes were reported in some cases with pharmacokinetic/pharmacodynamic optimization strategies, including higher dosing regimens, prolonged infusion, or combination antimicrobial therapy. Factors contributing to the observed in vitro–in vivo discordance included neonatal pharmacokinetic variability, bacterial heteroresistance, inoculum effects, diverse resistance mechanisms, and host-related factors such as prematurity and immune immaturity.Conclusions Meropenem shows unpredictable clinical effectiveness in neonatal CRKP infections, and conventional MIC-based antimicrobial susceptibility testing does not reliably predict therapeutic outcomes in this population. Management strategies should integrate resistance mechanism profiling, individualized pharmacokinetic/pharmacodynamic optimization, and host-specific clinical considerations rather than relying solely on laboratory susceptibility results.