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BACKGROUND Limited treatment options complicate management of infections with New Delhi metallo-β-lactamase (NDM)-producing organisms. We assessed the efficacy of combination therapy with meropenem (MEM) and cefmetazole (CMZ) against NDM-producing Enterobacteriaceae. MATERIALS AND METHODS Twelve E. coli clinical isolates harbouring blaNDM-1 along with a positive control E. coli BAA-2469 harbouring blaNDM-1 were studied. Minimum inhibitory concentrations (MICs) of MEM, ertapenem (ERT), and CMZ were determined by broth microdilution. Checkerboard and time-kill assays were performed to confirm the in vitro efficacy of the MEM/CMZ combination. Scanning electron microscopy, kinetic studies, and whole genome sequence analysis were used to determine the antimicrobial resistant mechanisms. RESULTS MICs of MEM, ERT, and CMZ in monotherapy ranged from 8 to 32, 16 to 128, and 32 to 512 μg/mL, respectively. In checkerboard, MEM/ERT resulted in no synergy, whereas MEM/CMZ showed a synergistic effect in all the tested isolates. Furthermore, the MIC of MEM in combination decreased by 2- to 8-fold compared to that of MEM alone. The time-kill study revealed a bactericidal effect in 4 out of 13 isolates at 24 hours. Scanning electron microscopy showed spheroidisation of the bacterial cell in the MEM/CMZ combination, which was not observed in single antibiotic conditions. The kinetic studies indicated a better activity of CMZ to ERT as an antagonist for NDM-1. Whole genome sequence analysis did not reveal any explainable differences between isolates susceptible to the combination therapy and those not susceptible to combination therapy. CONCLUSION In vitro studies showed the potential effectiveness of MEM/CMZ combination therapy against NDM-producing organisms.