Background: The objective of this study was to develop solid lipid nanoparticles (SLNs) of poorly water soluble anti-hyperlipidemic drugs-Ezetimibe in combination with Simvastatin. Methods: This study describes a 32 full factorial experimental design to optimize the formulation of drug loaded lipid nanoparticles (SLN) by the high speed homogenization technique. The independent variables amount of lipid (GMS) and amount of surfactant (Poloxamer 188) were studied at three levels and arranged in a 32 factorial design to study the influence on the response variables- particle size, % entrapment efficiency (%EE) and cumulative drug release (% CDR) at 24 h. Results: The particle size, % EE and % CDR at 24 h for the 9 batches (B1 to B9) showed a wide variation of 104.6-496.6 nm, 47.80-82.05% (Simvastatin); 48.60-84.23% (Ezetimibe) and 54.64-92.27% (Simvastatin); 43.8-97.1% (Ezetimibe), respectively. The responses of the design were analysed using Design Expert 10.0.2. (Stat-Ease, Inc, USA), and the analytical tools of software were used to draw response surface plots. From the statistical analysis of data, polynomial equations were generated. Optimized formulation showed particle size of 169.5 nm, % EE of 75.43% (Simvastatin); 79.10% (Ezetimibe) and 74.13% (Simvastatin); 77.11% (Ezetimibe) %CDR after 24 h. Thermal analysis of prepared solid lipid nanoparticles gave indication of solubilisation of drugs within lipid matrix. Conclusion: Fourier Transformation Infrared Spectroscopy (FTIR) showed the absence of new bands for loaded solid lipid nanoparticles indicating no interaction between drugs and lipid matrix and being only dissolved in it. Electron microscope of transmission techniques indicated sphere form of prepared solid lipid nanoparticles with smooth surface with size approximately around 100 nm.