BACKGROUND Resistant starch is a novel type of dietary fiber that can be considered as a natural polymer carrier with potential development prospects in the field of oral colonic release preparations since it can be degraded by bacteria in the large intestine. MATERIAL AND METHODS In this study, oral resistant starch-drug-loaded microspheres were prepared by spraydrying, and the response surface method was used to optimize the process based on the encapsulation efficiency. RESULTS The optimal preparation process conditions for the resistant starch-aspirin-loaded microspheres were as follows: core material: wall material ratio of 1: 1.98, chitosan solution concentration of 1.98%, and spray drying air inlet temperature of 130.45°C resulted in a reliable entrapment efficiency of 68.96%. Infrared spectroscopy analysis indicated that the encapsulated aspirin-starch microspheres did not differ significantly from the original resistant starch material. The ultrastructure of the drug-loaded microspheres was evenly wrapped with the capsule core and appeared as smooth spheres. The combination of resistant starch, aspirin, and chitosan resulted in a cross-linking reaction that reduced the overall gelatinization temperature compared with the original starch material alone. The light transmittance of the drug-loaded microspheres was slightly higher than that of the original resistant starch, while digestibility was similar to that of the resistant starch, indicating that the release would exist in the environment of the large intestine. CONCLUSIONS This study provides pivotal insights into the development of resistant starch in the field of colonic release preparations.