Due to their biocompatible and eco-friendly properties, natural polymers have attracted significant attention as controlled drug delivery carriers. In this paper, a facile method is presented for preparing pH-sensitive microspheres via acidic esterification between sodium alginate (SA) and hydroxypropyl methylcellulose (HPMC). The resulting microspheres were characterized by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). To evaluate the potential applications of microspheres as a drug carrier, the controlled release of a model drug—diclofenac—was examined. The SEM analysis revealed that the microbeads were spherical with a relatively smooth outer surface and porous inner network structure. The drug release experiments indicated that the cumulative release of diclofenac was less than 1% in an acidic medium, whereas it was close to 100% within 3 h in a pH 6.8 phosphate buffer saline solution. These results demonstrated that the SA/HPMC microspheres are promising candidates as pH-sensitive drug delivery system.