Natural products have been pivotal in treating mycobacterial infections with early antibiotics such as streptomycin, forming the foundation of tuberculosis therapy. However, the emergence of multidrug-resistant and extensively drug-resistant Mycobacterium species has intensified the need for novel antimycobacterial agents. In this review, we revisit the historical contributions of natural products to antimycobacterial drug discovery and highlight recent advances in the field. We assess the application of molecular networking and the exploration of unculturable bacteria in identifying new antimycobacterial compounds such as amycobactin and levesquamides. We also highlight the role of semisynthesis in optimizing natural products, exemplified by sequanamycins and spectinomycin analogs that evade M. tuberculosis' intrinsic resistance. Finally, we discuss emerging technologies that are promising to accelerate the discovery and development of next-generation antimycobacterial therapies. Despite ongoing challenges, these innovative approaches offer renewed hope in addressing the growing crisis of drug-resistant mycobacterial infections.