Background: Drug resistance is still the major threat to global tuberculosis (TB) control, and drug-resistant (DR) Mycobacterium tuberculosis strains have become the main challenge worldwide. Although clofazimine (CFZ) has been traditionally used to treat leprosy, there has recently been interest in the use of CFX (a Group 5 agent) to treat MDR-TB and its use might shorten MDR-TB treatment to 9 month. Meropenem (MPM) and amoxicillin (AMX) are the family of β-lactam antibiotics. M. tuberculosis has traditionally been considered resistant to the β-lactams, there is emergeing evidence that meropenem/clavulanate can have anti-tubercular activity relevant to the treatment of XDR-TB. However, the mechanisms of resistance to these drugs are poorly understood. Therefore, we investigated the molecular basis of clofazimine, meropenem, and amoxicilin resistance using clinical isolates. Methods: We have selected 54 XDR isolates from the TB Specimen Bio-bank, Masan National Tuberculosis Hospital (MNTH). We obtained minimal inhibitory concentration (MIC) of CFZ, MPM, and AMX by resazurin microtiter assay (REMA). Then, whole genome sequencing (WGS) or target sequencing to identify possible mutations associated with CFZ, MPM, and AMX resistance. Results: We found that one of 46 isolates (2.17 %) of CFZ-R mutant, 86.96 % (40/46) of MPM-R, and 93.48 % (43/46) of AMX-R mutants. Particularly, CFZ-R mutant had mutation in gene. Conclusions: Mutations in Rv0678 are a major mechanism of CFZ resistance. Although we were not detected previously reported mutation region of CFZ-R, we detected minor mutation region. Our findings expect useful information for rapid detection of drug-resistance or mechanism of clofazimine resistance.