Background: Self-care practice is an integral and efficient part of the comprehensive management of diabetes that could be influenced by various sociodemographic, clinical, and lifestyle factors. Objective: The study aimed to assess diabetes self-care practice and its determinants among adults with diabetes on follow-up at Yirgalem general hospital, Yirgalem, Sidama, Ethiopia. Methodology: An Institution based cross-sectional study was conducted from February 15 to May 10, 2022 at Yirgalem general hospital on 297 randomly selected adults with diabetes on chronic care follow-up. Face-to-face interview using a pre-tested structured questionnaire and chart review was utilized to collect data. Descriptive analysis was done to determine the magnitude of self-care practice. Bivariate and multivariate Binary logistics regression was performed to determine predictors of self-care practice at α=0.05, using an adjusted odds ratio and 95% confidence interval. Association with p-value <0.05 was considered statistically significant. Result: The overall self-care practice among diabetic patients was 59.4%. Based on the domains of care, 15(5%) had good self-glucose monitoring care, 228(76.5%) had good exercise self-care, 268(89.9%) had good dietary self-care, 228(76.5%) had good foot self-care, and 260(87.2%) had good diabetic medication adherence. Residence area (AOR=2.992, 95% CI; (1.251, 7.153)) and ownership of glucometer (AOR=2.273, 95% CI; (1.083, 4.772)) were statistically significant predictors of good self-care practice among diabetic patients. Conclusion: The overall good practice of diabetic self-care in this study was low. Marital status, place of residence, and ownership of a functional glucometer were statistically significant predictors of good diabetic self-care. Targeted intervention addressing those patients coming from a rural area to increase the awareness and practice of self-care as well as promotion of ownership of glucometer and counseling on the importance of self-glucose monitoring is recommended.