Gallinamide A, originally isolated with a modest antimalarial activity, was subsequently reisolated and characterized as a potent, selective, and irreversible inhibitor of the human cysteine protease cathepsin L. Molecular docking identified potential modifications to improve binding, which were synthesized as a suite of analogs. Resultingly, this current study produced the most potent gallinamide analog yet tested against cathepsin L (<b>10</b>, <i>K</i><sub>i</sub> = 0.0937 ± 0.01 nM and <i>k</i><sub>inact</sub>/<i>K</i><sub>i</sub> = 8 730 000). From a protein structure and substrate preference perspective, cruzain, an essential <i>Trypanosoma cruzi</i> cysteine protease, is highly homologous. Our investigations revealed that gallinamide and its analogs potently inhibit cruzain and are exquisitely toxic toward <i>T. cruzi</i> in the intracellular amastigote stage. The most active compound, <b>5</b>, had an IC<sub>50</sub> = 5.1 ± 1.4 nM, but was relatively inactive to both the epimastigote (insect stage) and the host cell, and thus represents a new candidate for the treatment of Chagas disease.