Background. Hypertension prevalence is continuously rising and is projected to be 1.56 billion cases by the year 2025. Despite the great progress made in the treatment of hypertension, many patients still do not achieve optimal results and experience devastating complications due to uncontrolled high blood pressure. Objective. The aim of this study is to assess self-care practice and associated factors among hypertensive patients. Methods. An institution-based cross-sectional study was conducted at Debre Tabor Referral Hospital, Northwest Ethiopia, from October to November 2020. A single population proportion formula and systematic random sampling technique was used to recruit 392 study participants. The data were entered to Epi-Info software version 7.1 and then exported to SPSS version 23 for analysis. A descriptive statistic was expressed as percentage, frequency, and mean. Finally, multivariable logistic regression was used to identify factors associated with dependent variable using a p value of <0.05. Results. A total 392 eligible hypertensive patients participated in the study. The self-care practice among hypertension patients was found to be 54.1%. Urban residency (AOR = 2.17; 95% CI, 1.2–3.9), social support (AOR = 2.12; 95% CI, 1.13–3.39), good knowledge (AOR = 1.83; 95% CI, 1.15–2.91), age between 40 and 64 (AOR = 3.15; 95% CI, 1.19–8.3), age ≥65 (AOR = 3.81; 95% CI, 1.35–10.7), and stress control (AOR = 1.6; 95% CI, 1.06–2.67) were predictors of hypertension self-care practice. Conclusion and Recommendation. The study revealed that almost one out of two hypertension patients had good hypertension self-care practice. Good social support, age greater than 40 years, urban residency, good basic knowledge, and having stress control were positively associated with hypertensive self-care practice.