Paromomycin has been shown to have antileishmaniasis activity; however, its clinical use is restricted to some content owing to its poor skin penetration. To identify innovative methods of dermal administration of paromomycin and controlling the release delivery system, paromomycin was loaded into the solid lipid media as nanoparticles. Type of the method; microemulsion or solvent diffusion, the type of lipid; cetyl palmitate or stearic acid, were comparatively investigated on the average diameter, size distribution and entrapment efficiency of the lipid nanoparticles to maximize entrapment efficiency, reduce the particle size and its distribution. Three quantitative factors, paromomycin content, weight fraction of Tween 80 and drug to lipid ratio, were also investigated at two levels for Solid Lipid Nanoparticles (SLNs) formulation in a fractional factorial design. The results indicated that microemulsion was the most efficient method and stearic acid was the preferred lipid for SLNs formulation. The average size of the particles was reduced to 299.08 nm and the entrapment efficiency was enhanced from immediate release to 24 h.