Cutaneous Leishmaniasis (CL) is a disease caused by Leishmania parasites. Pentavalent antimonials are the leading treatment for CL despite their toxicity. In addition, the response of some Leishmania species to pentavalent antimonials is increasingly poorer, and therefore more potent therapeutic alternatives are needed. Arnica montana L., is a traditional medicinal plant commonly used for the topical treatment of superficial inflammatory conditions [1]. Arnica tincture (AT) and isolated Arnica sesquiterpene lactones (STLs) have antileishmanial activity [2], [3]. In this work, we studied the in vitro cytotoxicity and antileishmanial activity of AT and STLs against both L. braziliensis and L. tropica. The in vivo therapeutic effect of AT was studied in hamsters experimentally infected with L. braziliensis and L. tropica. Furthermore, various semisolid Arnica preparations were also evaluated against L. braziliensis. The STLs and the AT possess a very high in vitro activity against both Leishmania species with EC50 values ranging from 1.9 to 5.9 µg/mL. The AT was not cytotoxic for macrophages, fibroblasts, and hepatic cells. The therapeutic response of hamsters infected with L. braziliensis to AT was 87.5% (19.2 µg STL/2 x day/60 d), 72.7% (19.2 µg STL/1 x d/60 d), and 67% (38.4 µg STL/1 x d/60 d). In turn, the response in hamsters infected with L. tropica was 100% when treated at 19.2 µg STL/2 x day/60 d and 71% at a dose of 38.4 µg STL/1 x d/60 d. These results are promising and encourage the continuation of clinical trials with AT in CL patients.