To enhance the solubility and in vitro dissolution of fluticasone propionate (FP), a novel approach was developed with mechanochemical treatment. The order of solubilizing effect of β-CD derivatives was observed as HP-β-CD-SBE-β-CD-β-CD-HE-β-CD, consequently, HP-β-CD showed the highest stability constant. To further improve FP solubility, FP and HP-β-CD were grinded using a roll mill, the optimal conditions, determined through single factor experiments, were as follows: rotation frequency of 60 Hz; milling time of 6h. mass ratio of 1: 7. In comparison with pure FP, a 280-fold increase in solubility and a 2.15-fold higher dissolution rate of ground mixture was obtained. The characterization of FP and HP-β-CD complexes had been analyzed by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and fourier transform infrared spectroscopy (FT-IR). The results suggested that the interaction between FP and HP-β-CD was strengthened and an amorphous ground mixture was gained. After stored for 60 days, the ground mixtures were stable both chemically and physically.