The aims of this study were to develop a nanostructured lipid carrier (NLC) system and optimize an appropriate NLC formulation using design of experiments (DOE). The results showed that the formulation containing glycerol monostearate (GMS) 0.35 g, stearic acid (SA) 0.50 g and isopropyl myristate (IPM) 0.65 g was optimal with entrapment efficiency (%EE) (59.21%), particle size (233.7nm) and zeta potential (-41.26 mV). Moreover, solid lipid (GMS, SA) and liquid lipid (IPM) had significant impact on NLC characteristics. The positive effect on the %EE was due to the interaction between GMS and IPM, and SA and IPM. The optimal formulation EWH-NLC at concentration 125 µg/ml expressed the highest inhibitory activity against NO production in RAW 264.7 macrophages with no cytotoxicity. The release profile of EWH-NLC in the cream base exhibited sustained release behavior that best fitted with Higuchi model. These results suggest that the NLC is a suitable carrier for EWH in topical application with a sustained-release profile.