The aim of this work is the isolation of anti-leishmanial compounds from the ethyl acetate extracts of the bark of Hedyosmum angustifolium. We have successfully isolated and characterized five sesquiterpenes: one new compound (oxyonoseriolide, 1), one compound isolated for the first time from a natural source (hedyosmone, 2), and three known sesquiterpenes (onoseriolide, 3; chloranthalactone A, 4; and spathulenol, 5) that had not been previously isolated from H. angustifolium. The biological activities of 15 showed that onoseriolide (3) was the most active compound against axenic amastigotes from Leishmania amazonensis and L.infantum. Moreover, it was still active on the intramacrophagic amastigotes of L.infantum. The isolated compounds have also been tested on Plasmodium falciparum and against various mammalian cell lines.