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Background Self-care practice of asthma is the strategy for asthma symptom control and future reduction of exacerbation, but it is poorly implemented in clinical settings due to the patients, professionals, and organizational related factors. Therefore, the study aimed to assess the self-care practice and associated factors among adult asthmatic patients at Northwest Amhara referral hospitals. Methods Institution-based cross-sectional study was conducted among asthmatic patients on follow-up care at Northwest Amhara Regional State referral hospitals from February 1st, 2020 to March 30, 2020. Data were collected through an interviewer-administered technique. Asthma self-care practice tool was used to measure the outcome. Data were entered into EPI info version 7 and exported to SPSS version 22 for analysis. A binary logistic regression analysis was used. In multivariable logistic regression analysis, those independent variables having p value Results A total of 470 participants enrolled in the study with a response rate of 100%. The proportion of good self-care practice among asthmatic patients was found to be 42.3%. The study revealed that; age group ≥ 55 years, having a co-morbid illness and borderline anxiety, having no social support, and drinking alcohol were significantly associated with poor asthma self-care practice. Conclusions Poor-self care practice in this study was high. Efforts need to be implemented for asthmatic patients with older age, having co-morbid illness and borderline anxiety, having no social support, and drinking alcohol.