Silymarin (SLM) is a hepatoprotective herbal drug characterized by low aqueous solubility and, consequently, low oral bioavailability. The objective of this study was to enhance the physiochemical properties of SLM, through preparation and optimization of lyophilized nanosuspension tablets (LNTs). LNTs were prepared by sonoprecipitation technique followed by a freeze-drying process using both polyvinyl alcohol (PVA) as stabilizer and binder, and mannitol as cryoprotectant and disintegrating agent. 32 full factorial design (FFD) was applied to study the effect of independent variables at different concentrations of both PVA (X1) and mannitol (X2) on the dependent variables that included mean particle size (Y1), disintegration time (Y2), friability % (Y3) and time required to release 90% of the drug (Y4). Several physicochemical evaluations were implemented on the optimized formula; for instance differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, scanning electron microscopy and transmission electron microscopy. These analyses demonstrated that the drug was in an amorphous state, stable in nanosize range and displayed no chemical interaction with the polymer. Moreover, the optimized formula had highly porous structure, rapid disintegration, friability with less than 1% and noticeable improvement in saturation solubility and dissolution rate.