Leishmaniasis is a worldwide disease which mainly occurs in the poorest countries. The diseases affect millions of people causing high morbi-mortality. Despite cutaneous leishmaniasis does not cause death, it is highly associated with social stigma and discrimination. Lack of treatments, decreased efficacy, side effects and high costs, emphasize the need for advances in the development of new and better drugs. Natural products remain an important source of novel chemical structures. The chromane moiety is widely distributed in nature and has been detected in flavonoids, coumarins, alkaloids and other types of natural products. Therefore, a lot of biological activities are reported for compounds containing this moiety, including anticancer, antiparasite, and anti-inflammatory activity. On the other hand, Sapindus saponaria resin contain saponin-type hederagenin and has been employed in traditional medicine as an antihelmintic, but these types of compounds are also reported as leishmanicidal. In this work, we report the antiparasitic activity of mixtures of saponin- and chromane hydrazone hybrids – a hybrid molecule containing saponins and chromanes coupled with hydrozones. The therapeutic efficacy of an ointment containing various combinations of these compounds were tested in hamsters infected with Leishmania panamensis and L. braziliensis. The formulation prepared with saponins and chromanes/hydrazones in 1:1 ratio showed 100% cure of hamsters. These results provide important basis to suggest that these formulations are good candidates for development of a new alternative therapy for cutaneous leishmaniasis.