The purpose of this study was to enhance the anti-leishmanial efficacy of miltefosine (MTF) and reduce its toxic effects by loading it into nanostructured lipid carriers (NLCs). Micro-emulsion technique was used to prepare MTF-loaded NLCs. The optimized NLCs were characterized in terms of various physicochemical parameters including particle size, poly dispersity index (PDI), zeta potential, transmission electron microscopy (TEM), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) technique. In vitro and in vivo assays were performed to evaluate the potential of NLCs as an effective nanocarrier system for oral delivery of MTF in Cutaneous Leishmaniasis. The optimized MTF-loaded NLCs exhibited mean particle size of 160.8 ± 5.3 nm with narrow PDI and high incorporation efficiency (IE%) of 96.17 ± 1.3%. MTF-loaded NLCs demonstrated slow release of the incorporated drug as compared to the drug solution. The optimized formulation showed significant decrease in hemolytic potential, 2.5folds increase in anti-leishmanial efficacy and 6fold decrease in macrophage cytotoxicity as compared to MTF solution, in vitro. Macrophage uptake study confirmed passive targeting ability of MTF-loaded NLCs. In-vivo analysis demonstrated enhanced anti-leishmanial effect of the MTF-loaded NLCs and better pharmacokinetic profiles with no gastrointestinal (GI) toxicity. NLCs are potential nanocarriers for the oral delivery of MTF with enhanced anti-leishmanial activity, better safety profile and reduced hemolytic potential.