Introduction: Diabetic foot ulcer is a serious and disabling complication of diabetes mellitus that consists of lesions in the deep tissues resulting in lower extremity amputations. The incidence of diabetic foot ulcers has increased due to an increased prevalence of diabetes mellitus. This study assessed the knowledge and practice of diabetic foot self-care among diabetic patients attending Dessie referral hospital. Methods: A facility-based explanatory sequential mixed method was used from April 03/ 2019 to May 09/2019. The quantitative method employed an institutional-based crosssectional study design using a structured questionnaire. A simple random sampling technique was employed to select the study participants. Descriptive and inferential statistics were made using the statistical package for social sciences version 20. Then, a phenomenological study was employed among key informants and content analysis was performed. Results: Sixty-eight (19.8%) of patients with diabetes developed complication, among them 97 (28%) had foot ulcer. Nearly two-third (217 (61.3%): 95% CI (57.6-68.3%)) and 134 (39%; 95% CI:34.3-45.1%) of patients with diabetes had good knowledge and practice on diabetic foot self-care, respectively. Diabetic nephropathy ((AOR): 0.03, 95% CI (0.00-0.27)) was associated with knowledge on foot self-care. Practice of foot self-care was associated with female ((AOR: 2.07, 95% CI (1.04-4.12)), age 21-30 ((AOR: 6.42, 95% CI (1.54-26.8)), 31-40 years ((AOR: 7.4, 95% CI (1.42-39.05)), 41-50 years ((AOR: 8.4, 95% CI (1.4-50.6)), single ((AOR: 0.35, 95% CI (0.150-0.81)), living in rural ((AOR: 0.31, 95% CI (0.18-0.545)) and no comorbidity ((AOR: 0.406, 95% CI (0.18-0.88)). Key informants were not compliant, confused and negligent to foot self-care. Conclusion: Nearly two-third and more than one-third of patients with diabetes had good knowledge and practice on diabetic foot self-care, respectively. Patients lack proper knowledge regarding self-care and how it is practiced. Patient education and proper management of diabetic foot ulcers are recommended to reduce, delay, or prevent complications.