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Although diloxanide is a drug of choice for treating asymptomatic amoebiasis, its mechanism of action (MOA) remains unclear. This review aims to shed light on the current understanding of the effectiveness and MOA of diloxanide in treating amoebiasis . It involves analysis of articles, retrieved from PubMed, Google Scholar and EBSCOhost, on diloxanide and the treatment of Entamoeba histolytica infection. Diloxanide is used in an ester form, which allows its high luminal concentration and greater efficacy than metronidazole in the management of asymptomatic amoebiasis. The current understanding of the action of diloxanide is based on its structural similarity to chloramphenicol at dichloroacetamide group. It acts against protein synthesis in E. histolytica trophozoites, blocking their conversion to more virulent and invasive cyst forms. Furthermore, it has a parasite clearance rate of 81-96% and treats amoebic abscesses when combined with metronidazole and chloroquine. Nevertheless, it is associated with adverse events such as flatulence, anorexia, headache and urticaria. Diloxanide is efficacious against amoebiasis but there is a need to explore its structure-activity relationship.The study suggests future directions, including novel drug formulations, diagnostic improvements, and combination regimens to enhance treatment outcomes and mitigate relapse associated with the use of diloxanide., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)