Response surface methodology (RSM) using the central composite rotatable design (CCRD) model was used to optimize formulations of dihydroartemisinin nancistructured lipid carrier (DHA-NLC). The CCRD consisting of three-factored factorial design with three levels was used in this study The drug encapsulation efficiency (EE), drug loading (DL) percentage and particle size of DHA-NLC were investigated with respect to three independent variables including DHA concentration (XI), lipid concentration (X-2) and ratio of liquid lipid to total lipid (X-3). The result showed that the optimal formulation could be obtained from this response surface methodology The optimal formulation for DHA-NLC was composed of DHA concentration (X-1) of 1 g/l, lipid concentration (X-2) of 1% and ratio of liquid lipid to total lipid (X-3) of 0.1:1. DHA-NLC under the optimized conditions gave rise to the EE of (98.97 +/- 2.3)%, DL of (15.61 +/- 1.9) mean diameter of (198 +/-4.7) nm, polydispersity index (PI) of 0.146 and zeta potential value of (-21.6 +/- 1.3) mV TEM of the optimized NLC showed spherical particles. The in vitro experiments proved that DHA in the NLC released gradually over the period of 48 h. This study showed that the RSM-CCRD could efficiently be applied for the modeling of DHA-NLC. Published by Elsevier B.V.