| Summary: | Amoebiasis, a disease caused by the protozoan <i>Entamoeba histolytica</i>, represents a serious public health problem, mainly in developing countries. The first line of therapy for amoebiasis treatment is metronidazole (MTZ); however, clinical isolates of <i>E. histolytica</i> with resistance to MTZ and varying sensitivity to other antiamoebic drugs threaten the effectiveness of the prevention and treatment of this parasitic infection. Natural products stand out as a promising strategy to develop new, safe and more effective alternatives. In this study, we determined and compared the phytochemical profiles of <i>Agave tequilana</i>, <i>Agave angustifolia</i>, <i>Agave rhodacantha</i>, and <i>Agave maximiliana</i> and described their cytotoxic effect on <i>E. histolytica</i> trophozoites. The results show that the four Agaves kill <i>E. histolytica</i> in a species–time–dose-dependent manner. A morphologic analysis of the treated parasites showed evident morphological alterations suggestive of programmed cell death with nuclear alterations; it also highlighted the presence of rounded cells with protuberances/perforations in the membrane and cells that appeared to have exploded. The overall activity of Agave ethanolic extracts in <i>E. histolytica</i> can help provide new strategies to advance alternative treatments against amoebiasis.
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