Conventional chemotherapy of cutaneous leishmaniasis (CL) is based on multiple parenteral or intralesional injections with systemically toxic drugs. Aiming at a single-dose localized therapy, biodegradable PLGA (poly-(lactide-co-glycolide) microparticles loaded with 7.8% of an antileishmanial nitrochalcone named CH8 (CH8/PLGA) were constructed to promote sustained subcutaneous release. In vitro, murine macrophages avidly phagocytosed CH8/PLGA smaller than 6μm without triggering oxidative mechanisms. Upon 48-hour incubation, both CH8 and CH8/PLGA were 40 times more toxic to intracellular Leishmania amazonensis than to macrophages. In vivo, BALB/c were given one or three subcutaneous injections in the infected ear with 1.2mg/kg of CH8 in free or CH8/PLGA forms, while controls received three CH8-equivalent doses of naked PLGA microparticles or Glucantime. While a single injection with CH8/PLGA reduced the parasite loads by 91%, triple injections with free CH8 or CH8/PLGA caused 80% and 97% reduction, respectively, in relation to saline controls. Glucantime treatment was the least effective (only 36% reduction) and the most toxic as seen by elevated alanine aminotransferase serum levels. Together, those findings show that CH8/PLGA microparticles can be effectively and safely used for single-dose treatment of CL.