Sesquiterpene lactones are naturally occurring compounds mainly found in the Asteraceae family. These types of plant metabolites display a wide range of biological activities, including antiprotozoal activity and are considered interesting structures for drug discovery. Four derivatives were synthesized from estafietin ( ), isolated from (Asteraceae): 11βH,13-dihydroestafietin ( ), epoxyestafietin ( and ), 11βH,13-methoxyestafietin, ( ) and 11βH,13-cianoestafietin. The antiprotozoal activity against and of these compounds was evaluated. Epoxyestafietin was the most active compound against trypomastigotes and amastigotes (IC values of 18.7 and 2.0 µg/mL, respectively). Estafietin ( ) and 11βH,13-dihydroestafietin ( ) were the most active and selective compounds on promastigotes (IC values of 1.0 and 1.3 μg/mL, respectively). The antiparasitic activity demonstrated by estafietin and some of its derivatives make them promising candidates for the development of effective compounds for the treatment of Chagas disease and leihsmaniasis.