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Background: In Indonesia, the number of Type 2 diabetes cases is increasing rapidly, making it the third leading cause of death and among the leading noncommunicable disease healthcare expenditures in the country. Thus, there is a critical need for Indonesians with Type 2 diabetes to perform better self-care to optimize their health and prevent the onset of comorbidities. Purpose: This study was designed to investigate the influence of knowledge, depression, and perceived barriers on Type 2 diabetes self-care performance in Indonesia. Methods: A cross-sectional study was conducted on 185 patients with Type 2 diabetes, with demographic, diabetes history, obesity status, diabetes knowledge, depression, perceived barriers, and self-care performance data collected. The Indonesian version of the Revised Diabetes Knowledge Test, Depression Anxiety Stress Scale, Perceived Barrier Questionnaire and Self-Care Inventory-Revised were used. Descriptive, bivariate, and multiple linear regression analyses were performed. Results: Study participants were found to have moderate diabetes self-care performance scores. Annual eye checks, blood glucose self-monitoring, healthy diet selection, and regular exercise were the least common self-management techniques performed and were consistent with the perceived difficulties of the participants. Being illiterate or having an elementary school education (β = 4.59, p = .002), having a junior or senior high school education (β = 3.01, p = .006), having moderate depression (β = −0.92, p = .04), diabetes knowledge (β = 0.09, p = .006), and perceived barriers (β = 0.31, p < .001) were found to explain 40% of the variance in self-care performance. Educational level, depression, and perceived barriers were the strongest factors that impacted Type 2 diabetes self-care performance in this study. Conclusions/Implications for Practice: Nurses should not only provide diabetes education but also identify barriers to diabetes self-care early, screen for the signs and symptoms of depression, and target patients with lower levels of education. [ABSTRACT FROM AUTHOR]