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Trypanosomiasis and leishmaniasis are a group of neglected parasitic diseases caused by several species of parasites belonging to the family Trypansomatida. The present study investigated the antitrypanosomal and antileishmanial activity of chalcones and flavanones from <i>Polygonum salicifolium</i>, which grows in the wetlands of Iraq. The phytochemical evaluation of the plant yielded two chalcones, 2′,4′-dimethoxy-6′-hydroxychalcone and 2′,5′-dimethoxy-4′,6′-dihydroxychalcone, and two flavanones, 5,7-dimethoxyflavanone and 5,8-dimethoxy-7-hydroxyflavanone. The chalcones showed a good antitrypanosomal and antileishmanial activity while the flavanones were inactive. The EC₅₀ values for 2′,4′-dimethoxy-6′-hydroxychalcone against <i>Trypanosoma brucei brucei</i> (0.5 μg/mL), <i>T. congolense</i> (2.5 μg/mL), and <i>Leishmania mexicana</i> (5.2 μg/mL) indicated it was the most active of the compounds. None of the compounds displayed any toxicity against a human cell line, even at 100 µg/mL, or cross-resistance with first line clinical trypanocides, such as diamidines and melaminophenyl arsenicals. Taken together, our study provides significant data in relation to the activity of chalcones and flavanones from <i>P. salicifolium</i> against both parasites in vitro. Further future research is suggested in order to investigate the mode of action of the extracted chalcones against the parasites.