The pressing global challenges of parasitic diseases, particularly prevalent in tropical and subtropical regions, underscore the critical urgent need for innovative therapeutic strategies in identifying and developing new treatments. The immense chemical diversity inherent in nature has rendered natural product (NP) chemistry a promising avenue for the discovery of novel antiparasitic chemotypes. Despite challenges such as sourcing, synthetic complexity, and drug resistance, NPs continue to offer invaluable contributions to antiparasitic therapy. This review focuses on recent advancements in NP chemistry and their application in the development of antiparasitic therapeutics. Key highlights include the identification of new molecular targets such as enzymes, membrane proteins, and metabolic pathways in parasites, as well as the role of metabolomics, genomics, and high-throughput screening in accelerating drug development. Additionally, the exploration of microorganisms (including soil bacteria and fungi) and marine organisms as a latent reserve of bioactive compounds with potent antiparasitic activity is discussed. The review further examines emerging strategies such as chemoinformatics and combination and polypharmacology therapies, aimed at addressing the challenges of antiparasitic chemotherapeutic treatment and advancing the development of new and effective treatments. Ultimately, NP chemistry represents a frontier for the design of novel antiparasitic drugs, offering the potential for more effective and sustainable therapies for combating parasitic diseases.