Nanosuspensions are the dispersions of nanosized particles in a suitable vehicle prepared using surfactants or solubilizers to aid in nanosize distribution. Nanosuspension is best suited for dosage form development of poorly soluble drugs. According to the biopharmaceutical classification system, drugs with poor solubility fall either in BCS class II or BCS class IV. BCS class II drugs show poor solubility and good permeability; hence their bioavailability problems can be overcome by improving their solubility. Metaxalone is one such BCS class II drug from an oxazolidin-2-one class of centrally acting muscle relaxant drugs, indicated for relief of discomforts associated with acute, painful musculoskeletal conditions. Therefore, in present investigation, nanosuspension of Metaxalone has been formulated as an attempt to improve solubility and hence the overall bioavailability of Metaxalone. Media milling technique has been employed for nanosuspension preparation. Surfactant concentration (Poloxamer 407) and stirring time has been optimized using 32 factorial design to achieve desired particle size and saturation solubility responses as dependent variables. The particle size (PS) of 215.3 nm and maximum saturation solubility (SS) of 2805μg/ml was obtained as suggested solutions from factorial design which was further confirmed using check point analysis. Interaction of surfactant concentration and stirring time and their effect on particle size and saturation solubility was predicted using the contour plots and response surface plots. The optimized formulation showed around 99% metaxalone in vitro dissolution in comparison to around 46% dissolution from SKELAXIN® tablet at 30 minutes. These methodologies could therefore be employed successfully to improve solubility of any BCS class II drug and to predict effects and interactions of many experimental variables at the same time.