Introduction: Diabetes self-care is important to maintain optimal glycemic control and prevent debilitating and costly complications. Diabetes self-care may be improved through the identification of individual and group barriers to regimen adherence and subsequent development of specific plans to overcome these barriers. This study assessed the self-care practice and associated factors among type 2 diabetes patients attending their treatment at Dessie Referral Hospital, Dessie, North-Eastern Ethiopia. Methods: The study employed parallel mixed methods design which followed a cross-sectional interview and in-depth interview methods respectively from September to October 2019. The collected data were subjected to descriptive and inferential analysis for the quantitative part and a thematic analysis for the qualitative part. The protocol for this study was ethically approved (CMHS/013/519/12). Results: A total of 328 type 2 diabetes patients participated in the study of which 50.3% reported good self-care practice. Being in the age category of 60–69 years old (AOR = 0.334, 95% CI (0.135, 0.951)), being ≥ 70 years old (AOR = 0.359, 95% CI (0.135,0.951)), having complications (AOR = 1.956, 95% CI (1.172, 3.262)), having co-morbidity (AOR = 0.443, 95%CI (0.262, 0.749)) and diabetes education (AOR = 2.684, 95%CI (1.633,4.412) were significantly associated with good diabetes self-care. Accessibility, social support, knowledge and beliefs and diabetes related morbidities were identified as barriers to diabetes self-care by the patients. Conclusion: The findings from this study revealed that only half of the type 2 diabetes patients who participated in this study reported good self-care practice. Different factors including diabetes education were significantly associated with good diabetes self-care according to the quantitative study. This was supported by the findings from the qualitative part and thus the recommendation to strengthen diabetes health education to patients and their families.