Altrenogest (ALT) is oral progestin with poor solubility (~10 μg/mL) and rapid metabolism in vivo, which severely constraints on clinical effectiveness. Nanosuspension drug delivery systems (NS) can reduce the drug particles to nanometer size and improve the solubility and bioactivity of insoluble drugs. The factors and mechanism of altrenogest nanosuspension (ALT-NS) formation were analyzed and investigated using the anti-solvent precipitation method and its quality was evaluated. The preparation process and prescription composition were analyzed and optimized using single factor experiments and the central composite design-response surface methodology (CCD-RSM), and the experiments of characterization, chemical structure analysis, crystalline shape examination, physical stability and release experiments in vitro were applied to evaluate the quality of ALT-NS. The optimal prescription and process were determined as follows: altrenogest 0.4wt%, sodium dodecyl sulfate (SDS) 25 mg/mL, hypromellose (HPMC) 4 mg/mL, stirring speed of 1000 r/min, and stirring time of 10 minutes. The formulation was a light yellow clarified liquid, and the drug particles were in the form of spherical particles with an average particle size of 104.87±1.10 nm, PDI (particle size distribution index) of 0.19±0.01, and Zeta potential of -37.87±0.81 mV, the drug was transformed from crystalline to amorphous state, and the use of freeze-drying technology to make ALT-NS into freeze-dried powder could further improve its physical stability. The cumulative release of the preparation group in vitro was 98.4% at 72 h,which was about 1.54 times higher than that of the original group, showing high efficiency and smooth drug release. In conclusion, the optimization of the prescription composition and preparation process of ALT-NS using the anti-solvent precipitation method can significantly reduce the physical size and specific surface area of ALT, improve the dissolution and release efficiency of ALT, and the formulation has the efficient and fast drug release characteristics, which is expected to provide a reference for the clinical application of ALT-NS.