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This review focuses on recent innovations in protozoal disease treatment aimed at combating this growing challenge of drug resistance. The escalating prevalence of multidrug resistance among protozoal parasites, especially those responsible for widespread diseases such as malaria, leishmaniasis, and trypanosomiasis, is rapidly emerging as a grave threat to human health worldwide. This resistance undermines the efficacy of existing treatments, making it imperative to develop and explore novel therapeutic approaches. Diverse strategies, including the concept of hybrid drugs, the development of advanced analogs of existing drugs, and drug repurposing, have been employed to counter drug resistance by outmaneuvering the evolution of resistant parasites and restoring the effectiveness of treatments. In this review, we delve into the significant findings reported between 2020 and 2024, with the aim of providing an overview of the state of protozoal disease treatment, highlighting the progress made, exploring promising avenues for tackling these devastating diseases, and offering insights into future directions for overcoming the persistent challenge of drug resistance. Given that the emergence of drug resistance calls for a multifaceted approach to address protozoal infections, long\u2010term success depends on interdisciplinary research collaborations, equitable access to treatment, and appropriate drug resistance surveillance, in addition to the advancement of research and the development of therapeutic strategies described in this review.<\/jats:p>","DOI":"10.1002\/ardp.70029","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T06:36:26Z","timestamp":1753079786000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Combating Drug\u2010Resistant Protozoal Infections: A Review of Emerging Therapeutics"],"prefix":"10.1002","volume":"358","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2710-2724","authenticated-orcid":false,"given":"Anju A.","family":"Tom","sequence":"first","affiliation":[{"name":"Department of Chemistry Pondicherry University 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