Due to its low bioavailability and slow dissolution rate, the micronized spiramycin powder was thus prepared by the homogenate-antisolvent precipitation (HAP) process. The optimum micronization conditions of the HAP process were found to be as follows: precipitation temperature of 4.6 °C, precipitation time of 10 min, spiramycin concentration of 20 mg/mL, dripping speed of the added solvent into the antisolvent of 44 mL/h, antisolvent (water) to solvent (dimethyl sulfide (DMSO)) volume ratio of 7:1, and shear rate of 5000 rpm. With this HAP process, the mean particle size was 228.36 ± 3.99 nm. The micronized spiramycin was characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, high-performance liquid chromatography, and gas chromatograph analyses. In comparison with the raw drug, the chemical structure of micronized spiramycin was not changed. The dissolution rate experiments showed that the dissolution rate of the spiramycin was significantly increased after micronization.