Hybrid vinylthio-, vinylsulfinyl-, vinylsulfonyl- and vinylketo-benzofuroxans developed as anti-trypanosomatid agents, against Trypanosoma cruzi and Leishmania spp., have showed low micromolar IC(50) values. The synthetic route to access to these derivatives was an efficient Wittig reaction performed in mild conditions with polymer-supported triphenylphosphine (PS-TPP). Additionally, the benzofurozan analogues, deoxygenated benzofuroxans, were prepared using PS-TPP as reductive reagent in excellent yields. The trypanosomicidal and leishmanocidal activities of the benzofuroxan derivatives were measured and also some aspects of their mechanism of action studied. In this sense, inhibition of mitochondrial dehydrogenases activities, production of intra-parasite free radicals and cruzipain inhibition were studied as biological target for the anti-trypanosomatid identified compounds. The trypanosomicidal activity could be the result of both the parasite-mitochondrion function interference and production of oxidative stress into the parasite.