Purpose: The study aimed to design and develop an automated personalized self-care (APSC) program for patients with type 2 diabetes mellitus. The secondary aim was to present a clinical protocol as a mixed-method research to test the program effects. Methods: The APSC program was developed in the order of analysis, design, implementation, and evaluation according to the software development life cycle, and was guided by the self-regulatory theory. The content validity, heuristics, and usability of the program were verified by experts and patients with type 2 diabetes mellitus. Results: The APSC program was developed based on goal setting, education, monitoring, and feedback components corresponding to the phases of forethought, performance/volitional control, and self-reflection of self-regulatory theory. Using the mobile application, the participants are able to learn from educational materials, monitor their health behaviors, receive weekly-automated personalized goals and feedback messages, and use an automated conversation system to solve the problems related to self-care. The ongoing two-year study utilizes a mixed method design, with 180 patients having type 2 diabetes mellitus randomized to receive either the intervention or usual care. The participants will be reviewed for self-care self-efficacy, health behaviors, and health out-comes at 6, 12, 18, and 24 months. Participants in the intervention group will be interviewed about their experiences. Conclusion: The APSC program can serve as an effective tool for facilitating diabetes health behaviors by improving patients’ self-care self-efficacy and self-regulation for self-care. However, the clinical effectiveness of this program requires further investigation.