Sertraline hydrochloride is an antidepressant with limited bioavailability and solid lipid nanoparticles (SLN) is one of the approaches to improve bioavailability. This study describes a box behnken experimental design to optimize the formulation of sertraline hydrochloride loaded solid lipid nanoparticles (SLN) by the probe sonication method. For optimization, a three factors and two levels box-behnken design was applied to study the effect of independent variables (factors) i.e. drug to lipid ratio (X 1), surfactant concentration (X 2) and probe sonication time (X 3) on dependent variables (responses) i.e. particles size (Y 1), entrapment efficiency (Y 2). Polynomial equations were generated on the basis of statistical analysis of data. The particle size and % EE for the 13 batches (R 1 to R 13) showed a wide variation of 145-201 nm and 80.5-88.8 %, respectively. The physical characteristics of sertraline hydrochloride loaded SLN were evaluated using FT-IR, differential scanning calorimetry and X-ray diffraction. The results of the optimized formulation showed an average particle size of 130.6 nm and entrapment efficiency of 85.30 %.