<p> Purpose Tuberculosis (TB) remains a major global health concern, particularly due to the emergence of multidrug-resistant strains, highlighting the need for innovative therapeutic approaches. This study evaluated the efficacy of a novel liposomal formulation encapsulating antimicrobial peptides LL-37 and IDR-1018 against Mycobacterium tuberculosis (Mtb). The research explored whether liposomal encapsulation could improve the stability and antimicrobial effectiveness of these peptides, which show therapeutic potential but are limited by challenges in stability and delivery. Methods: A liposomal formulation using soy lecithin as the primary lipid carrier was developed to encapsulate LL-37, a naturally occurring antimicrobial peptide, and IDR-1018, a synthetic innate defense regulator. The encapsulation efficiency and biocompatibility, of the formulations were assessed using human-derived macrophages and A549 epithelial cells. Antimicrobial efficacy was evaluated against both drug sensitive and multidrug-resistant Mtb strains, comparing peptide-loaded liposomal formulations and with the free peptide. Results: High encapsulation efficiencies were achieved (80.31% for LL-37 and 92.86% for IDR-1018), and the formulations demonstrated excellent biocompatibility in cytotoxicity assays. While the liposomal formulations maintained comparable antimicrobial activity to free peptides, the results suggest opportunities to optimize peptide release and cellular uptake for enhanced efficacy. Conclusion: Liposomal encapsulation successfully improved the stability and biocompatibility of LL-37 and IDR-1018, providing a promising platform for further development. Future studies will focus on refining liposomal formulations and exploring peptide delivery strategies to maximize their therapeutic potential for TB.</p>