Background: Entamoeba histolytica is the causative agent of amoebic dysentery and hepatic abscesses. Despite the efficacy of metronidazole in alleviating infectious diseases, the global dissemination of drug-resistant parasites raises the possibility that Punica granatum could serve as an effective natural alternative treatment. Objective: To evaluate the effect of P. granatum methanolic and aqueous extracts of various parts against E. histolytica trophozoites in an in vitro setting. Methods: Various concentrations (0.14, 0.7, 1.4, and 2.8 mg/ml) of P. granatum extracts of the flowers, leafs, peels, and seeds were chosen for this purpose. A culture medium containing 0.05x106/ml E. histolytica trophozoites was treated with different concentrations of these extracts. The incubation period was 48 hours at 37°C. For every set, an untreated control was also performed. The standard medication metronidazole (17 μg/ml) was employed as a comparative control. Results: All parts of P. granatum showed high efficacy against E. histolytica trophozoites, but utilization of the methanolic extract proved to be quite effective compared to aqueous extract. Under a light microscope, several morphological changes were also seen. These include changes to the plasma membrane, reorganization of vacuoles that hold cell waste, and major changes to the cytoplasmic granules. Conclusions: The leaf, seed, flower, and peel extracts of P. granatum effectively inhibit the growth of E. histolytica trophozoites in vitro. The use of methanolic extract was more effective compared to the aqueous extract, and can be used as a natural alternative treatment for amoebic dysentery.