Epilepsy is thought to be caused by witchcraft, evil spirit, and God's punishment for sins in many developing countries. As a result, people with epilepsy and their families usually suffer from stigma, discrimination, depression, and other psychiatric problems. Thus, this study aimed to assess the quality of life and its associated factors among epileptic patients attending public hospitals in North Wollo Zone, Northeast Ethiopia. An institution-based cross-sectional study design was employed in this study. A simple random sampling technique was utilized. Health-related quality of life was measured based on the total score of the Quality of Life in Epilepsy Inventory (QOLIE-31) instrument. Data were entered into Epi-data 3.1 statistical package and exported to SPSS Version 20 for further analysis. Linear regression models were used to assess the relationship between quality of life and the independent variables. Statistically significant values were declared at a P-value of < 0.05. A total of 395 patients participated in the study making the response rate 98.5%. The mean age of the participants was 32.39 ±10.71 years. More than half, 199 (50.4%) of epileptic patients had an overall weighted average health related quality of life score of mean and above. Male sex (B = 4.34, 95%CI, 0.41, 8.27, P = 0.03), higher educational status (B = 7.18, 95%CI, 1.39, 13.00, P = 0.015) and age at onset of epilepsy (B = 0.237, 95%CI, 0.02, 0.45, P = 0.035) were associated with increased health related quality of life score. On the other hand, family history of epilepsy (B = -4.78, 95%CI,-9.24,-0.33, P = 0.035), uncontrolled seizure (B = -11.08, 95%CI,-15.11,-7.05, P < 0.001), more than 5 pre-treatment number of seizures (B = -4.86, 95%CI,-8.91,-0.81, P = 0.019), poor drug adherence (B = -11.65, 95%CI,-16.06,-7.23, P < 0.001), having moderate (B = -4.526, 95%CI,-8.59,-0.46, P = 0.029) to sever (B = -12.84, 95%CI,-18.30,-7.37, P < 0.001) anxiety and depression, believing that epilepsy is caused by evil spirit (B = -7.04, 95%CI,-11.46,-2.61, P = 0.002), drinking alcohol (B = -5.42, 95%CI,-10.72,-0.13, P = 0.045), and having other co-morbidities (B = -9.35, 95%CI,-14.35,-4.36, P < 0.001) were significantly negatively associated with the health related quality of life score among epileptic patients. Only around half of the epileptic patients have a good health-related quality of life. In addition, multiple variables including family history, uncontrolled seizure, and poor drug adherence were associated with quality of life among epileptic patients. Hence, targeting these variables in epilepsy management is recommended.