Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania. Curcumin (CUR) is a polyphenol with several biological properties, including antimicrobial effects. However, its low bioavailability remains a challenge, and nanoencapsulation may represent a useful strategy to overcome this limitation. This study aimed to evaluate, in vitro, the antipromastigote activity of free CUR and the antiamastigote effect of CUR nanoparticles and their association with antimoniate, as well as to elucidate possible mechanisms of action. Free CUR directly inhibited promastigote proliferation, with an IC₅₀ of 25 µM at 24 h. CUR induced mitochondrial hyperpolarization, increased the production of reactive oxygen species (ROS) and nitric oxide (NO), and enhanced lipid peroxidation and the accumulation of lipid droplets in promastigotes. These alterations were associated with autophagic and apoptotic processes, morphological and ultrastructural changes, DNA fragmentation, and cell cycle arrest. Free CUR also reduced the viability of BALB/c peritoneal macrophages, and this effect was attenuated after nanoencapsulation. Free CUR, CUR nanoparticles, and their association with antimoniate (AM) reduced both the percentage of infected macrophages and the number of intracellular amastigotes at all tested concentrations, with increased NO production observed at the highest concentrations of free CUR. Altogether, our findings suggest that CUR exerts leishmanicidal activity against promastigotes by disrupting oxidative metabolism and triggering autophagic and apoptotic pathways, while amastigote elimination appears to occur through mechanisms independent of oxidative stress.