AbstractLeprosy, caused by Mycobacterium leprae, remains a significant public health concern in several parts of the world in spite of the availability of multidrug therapy. The emergence of drug resistance and the prolonged duration of treatment highlight the urgent need for novel therapeutic strategies. Due to its highly reduced genome and obligate intracellular lifestyle, M. leprae relies on a limited set of essential proteins for survival, persistence, and pathogenicity, making these proteins attractive targets for drug discovery. This review provides a comprehensive analysis of key essential protein targets involved in critical biological processes such as cell wall biosynthesis, energy metabolism, DNA replication, transcription, translation, and stress response mechanisms. Particular emphasis is placed on enzymes and regulatory proteins that are indispensable for bacterial viability and show minimal homology with human proteins, thereby reducing the risk of host toxicity. By integrating current knowledge from genomics, proteomics, and computational drug discovery studies, this review highlights promising targets that could facilitate the development of selective and effective antileprosy agents. The identification and validation of these essential proteins may accelerate the design of novel therapeutics and contribute to improved management and eventual eradication of leprosy. Keywords Leprosy, Mycobacterium leprae, Multidrug Therapy, Proteins