A facile synthesis route to carboxyimidamide-substituted benzoxadiazoles and related derivatives was developed. A total of 25 derivatives were synthesized. They were evaluated for antileishmanial activity by inhibition of Leishmania donovani axenic amastigote growth using a fluorescent viability microplate assay. The most promising derivative (14) demonstrated an antileishmanial EC 50 of 4.0 µM, and it also showed activity in infected macrophages (EC 50 5.92 µM) without signs of cytotoxicity.