In the present study, to formulate captopril in a hierarchical porous structure of ZnO nanospheres by means of the soluble-starch-insertion method, state of drug carrier delivery toward oral route and the mode of delivery in suitable medium. Mesoporous ZnO nanospheres were synthesized by simple soluble-starch-insertion method, followed by loading of captopril using ultrasonic force. The materials were characterized by PXRD, SEM, FESEM, TEM, TGA, FT-IR, and BET analyses, and biocompatibility studies. Captopril-loaded porous ZnO nanospheres were evaluated as in vitro drug-release studies and its kinetic models. Crystallite plane arrangement, functional groups, materials morphology, and porosity of porous ZnO nanospheres were confirmed. Larger surface area and distribution in constrained pores on its surface make the nanospheres suitable for high drug loading of captopril. The ZnO nanocrystallites have given porous properties on the spherical surface leads to the drug adsorption. The loading and release studies (in vitro in simulated gastric and intestinal fluids) have shown that both were affected by the mesoporous nanospheres’ surface properties of the ZnO materials and its biocompatibility has also been proved. Therefore, the in vitro experiments have indicated the considerable promise of mesoporous ZnO nanospheres, fabricated by the soluble-starch-insertion method acting as a biocompatible carrier for the controlled delivery of captopril in oral route of administration.