Introduction: Quality of life is individuals' perceptions of their position in life in the context of the culture and value systems in which they live and about their goals, expectations, standards, and concerns. In the world, 70 million people suffer from epilepsy and 80% of epilepsy case was in the developing countries like Ethiopia. From a recent literature the prevalence quality of life in Ethiopia was 56.43. Due to different factor to contribute for the development of poor health-related quality of life that leads to the negative consequence on many patients with epilepsy; particularly in this study area, there were no studies done on the quality of life of epilepsy patients. Objective: To assess health related quality of life among epileptic patients and associated factors at Dessie referral Hospital, Amhara regional state, North East Ethiopia, 2020.Method: Facility-based cross-sectional study was conducted from April – June 2020. A systematic random sampling technique was employed to recruit a total of 415 study participants. Informed consent was taken for each participant and data was collected using the interviewer- administered questionnaire. Descriptive statistics was used to summarize the data while multivariate logistic regression analysis were employed to explore factors affecting the quality of life, p≤0.05was considered as statistically significant. Result: The response rate of this study was 92.5%. Among the total study participant, 56% of them were male and their mean age of participant was 35.5 (SD±14.4) years. Regarding occupation 33.3% of the participant was unemployed. Majority 95.8% of study participants had generalized seizure and 64.3% were taken two anti-epileptic drugs. From the total study participant, 12.2% and 37% were developing depression and anxiety respectively. The mean overall health related quality of life score of this study was 51.98 (95% CI: 41.9 – 62.06) out of 100. Age, educational status, marital status, occupation, residence, history of co-morbidity, family support and recreational activity was associated with health related quality of life (p≤0.05)Conclusion: The mean overall quality of life for epileptic patients at Dessie referral hospital was low. Hence, a concerted effort must be done to improve patient quality of life towards the provided healthcare services.