Electrohydrodynamic atomization (EHDA) process was exploited to prepare drug-loaded microparticles for colon-targeted drug delivery. Field emission scanning electron microscope results showed that the particles had a size of 1.3±0.7 μm. Differential scanning calorimetry (DSC) analyses and wide-angle X-ray diffraction analyses (XRD) results similarly demonstrated that the drug DS had been totally converted into an amorphous state in the EHDA microparticles with Eudragit® L-100 as the polymer matrix. Attenuated total reflectance Fourier transform infrared analysis disclosed that the secondary interactions presented between DS and Eudragit® L100 molecules. In vitro dissolution tests verified that the microparticles had a pH-dependent and sustained drug release profile. The present study provides an easy way for developing colon-targeted drug delivery microparticles.