Wet milling is a multifunctional and the most common method to prepare a drug nanosuspension for improving the bioavailability of poorly water-soluble drugs. A suitable way of preparing a high drug-loaded nifedipine nanosuspension using wet stirred media milling was critically investigated in the present study. Nifedipine, a poorly water-soluble drug, was selected as a model drug to enhance its dissolution rate and oral bioavailability by preparing an appropriate crystalline nanosuspension. Process parameters, such as milling media volume, milling speed and milling time, were optimized using the one variable at a time (OVAT) approach. A similar method was used to select an appropriate polymeric stabilizer and a surfactant from different categories of polymeric stabilizers (HPC SL, HPC SSL SoluplusRTM, KollidonRTM VA 64 and HPMC E 15) and surfactants (Poloxamer 407, Kolliphor TPGS and Docusate sodium). A systematic optimization of critical formulation parameters (such as drug concentration, polymer concentration, and surfactant concentration) was performed with the aid of the Box-Behnken design. Mean particle size, polydispersity index, and zeta potential as critical quality attributes (CQAs) were selected in the design for the evaluation and optimization of the formulation and validation of the improved product. The nifedipine nanosuspension that was prepared using HPC SL and poloxamer 407 was found to be most stable with the lowest mean particle size as compared to the formulations prepared using other polymeric stabilizers and surfactants. The optimized formulation was further spray-dried and characterized using the Fourier Transform Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), polarized light microscopy (PLM) and in-vitro dissolution studies. The results have shown no interaction between the drug particles and stabilizers, nor a reduction in the crystallinity of drug, nor an increase in the saturation solubility as well as rapid in vitro dissolution as compared to pure nifedipine crystals. Thus, the current study supports the suitability of the wet stirred media milling method and a combination of HPC SSL and poloxamer 407 as stabilizers for the preparation of nifedipine nanosuspension.