TB remains a significant global health burden due to protracted therapeutic courses, poor patient compliance, and toxicities associated with drug treatment, as well as concerns arising from increasingly prevalent multidrug-resistant and extensively drug-resistant strains of M. tuberculosis. The escalating prevalence of multidrug-resistant and extensively drug-resistant strains, compounded by the pathogen's extraordinary capacity to survive within host macrophages and pharmacologically impenetrable granulomas, has rendered conventional chemotherapy progressively insufficient, exposing an urgent and unmet need for transformative therapeutic innovation. This review comprehensively addresses that need by critically examining three converging paradigms redefining tuberculosis management: nanocarrier-based drug delivery systems, host-directed therapeutic strategies, and translational pharmacology. We systematically evaluate the structural and molecular determinants of Mycobacterium tuberculosis underpinning drug resistance and intracellular persistence, alongside an in-depth analysis of diverse nanocarrier platforms-polymeric nanoparticles, liposomes, solid lipid nanocarriers, dendrimers, biomimetic membrane-coated systems, and inhalable formulations, and host-directed approaches targeting autophagy, macrophage reprogramming, miRNA regulation, and antimicrobial peptide pathways. Receptor-mediated active targeting strategies, translational pharmacology frameworks, manufacturing challenges, and regulatory barriers are critically appraised, with an emerging roadmap encompassing artificial intelligence, CRISPR genomics, and mRNA-LNP vaccine platforms. This review equips researchers, clinicians, and pharmaceutical scientists with an integrated, evidence-based framework to accelerate the development and clinical translation of next-generation anti-tuberculosis therapeutics, ultimately contributing to the global ambition of ending tuberculosis.