Drug resistance in Mycobacterium tuberculosis (Mtb) is a complex phenomenon resulting from multiple coordinated molecular and genetic mechanisms that allow the bacterium to evade antimicrobial agents. Intrinsic resistance primarily stems from the unique architecture of the mycobacterial cell envelope, characterized by a dense, lipid-rich barrier that substantially limits antibiotic penetration and reduces intracellular drug concentrations. Additionally, enzymatic degradation mechanisms further diminish drug efficacy by inactivating antibiotics extracellularly. Acquired resistance is predominantly driven by spontaneous chromosomal mutations that modify drug targets or disrupt prodrug activation pathways, thereby reducing antibiotic binding affinity and therapeutic activity while preserving essential bacterial functions. Upregulation of drug targets and drug-modifying enzymes through genetic alterations leads to elevated thresholds for effective inhibition. Active efflux systems also play a critical role by transporting antibiotics out of the cell, lowering intracellular drug levels below therapeutic thresholds, and contributing to multidrug resistance. Collectively, these interrelated mechanisms establish a formidable defense network that complicates tuberculosis treatment and underscores the pressing need for novel therapeutic approaches to circumvent resistance and improve clinical outcomes.