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Background: Amoebiasis is caused by Entamoeba histolytica, which is a pathogenic species living on human colon tissues. The development of new drugs for anti-amebic are still very needed for clinical treatment. Objective: This aims to identify the compounds in Cratoxylum sumatranum for their anti-amoeba activity. Materials and Methods: In this study we used bioactivity-guided isolation and structural analysis to identified anti-amebic compounds from dichloromethane extract of Cratoxylum sumatranum stem bark. Their anti-amebic activity was determined by an in vitro cell-based assay against Entamoeba histolytica and an enzymatic assay on NAD kinase. Results: Two known compounds from the cage xanthone groups, namely cochinchinoxanthone (1) and cochinchinone D (2), were isolated. The structures of the cage xanthone compounds were established by extensive spectroscopic data analysis. Compound (1) showed the greatest level of anti-amebic activity both in cell-based and enzymatic assay, yielding IC 50 values of 4.57 and 12.17 µg/mL, respectively. In contrast, compound (2) yielded IC 50 values of 5.19 and 12.60 µg/mL, respectively. Conclusion: When considering the demonstrated anti-amebic activities, it becomes apparent that these compounds, isolated from Cratoxylum sumatranum stem bark, have the potential to be further developed into effective anti-amebic medicine against Entamoeba histolytica.