Aim: The aim of the present study was to design and evaluate solid lipid nanoparticles of Asenapine maleate (<2% bioavailability) to enhance its oral bioavailability and surface modification for brain targeting. Methods: A modified solvent injection method was used to produce Asenapine maleate loaded solid lipid nanoparticles. A RSM 3-factor, 3-level Box-Behnken design was applied to study the effect of three independent variables, concentrations of lipid (A), drug (B) and surfactant (C) on three dependent variables, particles size (Y1), entrapment efficiency (Y2), and drug release (Y3). 3-D surface response plots were drawn and optimized formulation was selected based on desirability factor. Then it was coated with tween 80 for ease of permeability through blood brain barrier due to intact absorption of solid lipid nanoparticles. Results: The results of coated optimized formulation showed average particle size of 108.9 nm, entrapment efficiency of 78.62%, and in vitro drug release of 98.88±0.102% at 36 hr at pH 7.4. Morphologically, particles were almost spherical in shape with uniform size distribution. Targeting of coated optimized formulation to brain after oral administration was confirmed by fluorescence microscopy studies on male albino wistar strain rats. This research also envisaged that there is a >85% cell viability up to 125µg/ ml concentration of coated solid lipid nanoparticles by MTT assay. Conclusion: Thus, the current study successfully designed, developed an optimized SLN formulation of Asenapine maleate using a 3-factor, 3-level Box-Behnken design for brain targeting to treat Schizophrenia by bypassing the first pass metabolism with enhanced oral bioavailability.