Leishmaniasis, trypanosomiasis, and malaria are a group of neglected tropical diseases present in tropical regions and they affect large numbers of people in developing countries. A series of thirteen coumaro-chalcones (A1-A13) were synthesized under solvent-free conditions and their in vitro anti-leishmanial, anti-plasmodial, anti-trypanosomal and cytotoxic activities were evaluated. One of these coumaro-chalcones, 3-[(2E)-3-(3-ethoxy-4-hydroxyphenyl)prop-2-enoyl]-2H-chromen-2-one (A12), is a new compound. Compounds 3-[(2E)-3-(3-hydroxyphenyl)prop-2-enoyl]-2H-chromen-2-one (A5), 3-[(2E)-3-(3-methoxyphenyl)prop-2-enoyl]-2H-chromen-2-one (A2) and 3-[(2E)-3-phenylprop-2-enoyl]-2H-chromen-2-one (A1) displayed strong inhibition against intracellular amastigotes of Leishmania panamensis with EC50 of 2.1 ± 0.1, 2.5 ± 0.2 and 3.7 ± 0.5 μM, respectively. In addition, Plasmodium falciparum was moderately inhibited by the coumarin-chalcone hybrids, particularly A12 (EC50: 15.0 ± 0.5 μM) and 3-[(2E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]-2H-chromen-2-one (A13) (EC50: 15.2 ± 1.1 μM). Remarkably, the coumaro-chalcone A5 (EC50: 18.7 ± 2.4 μM) exhibited an inhibition of the Trypanosoma cruzi intracellular amastigotes similar to the commercial drug Benznidazole (EC50: 14.5 ± 0.1 μM). These results support the therapeutic potential of coumaro-chalcone hybrids.