Objective: In the COVID-19 pandemic period, the effect of COVID-19 fear on quality of life was uncertain. This present study examined the effect of fear of COVID-19 on quality of life in patients with epilepsy through anxiety and depression. Methods: This single-center, cross-sectional study was conducted with a total of 319 adult patients with epilepsy. The mean age of the patients was 36.0 (± 11.1) years, and 53% were male. The mean duration of diagnosis was 16.0 (± 10.6) years, and more than half of the patients (52.4%) were using two and more antiepileptic drugs. Data were collected online between 15 December 2020 and 5 January 2021. COVID-19 Fear Scale, Beck Depression Inventory, Worry and Anxiety Questionnaire, and Epilepsy Quality of Life Scale-10 were used for data collection. Serial mediation analysis was conducted to determine the effect of COVID-19 fear on quality of life. Results: Although there was a significant correlation between them, the fear of COVID-19 did not directly affect the quality of life. The fear of COVID-19 increased anxiety and depression respectively, the increase in the mediators also decreased the quality of life. Conclusion: The fear of COVID-19 experienced by patients with epilepsy did not have a significant direct effect on the quality of life. However, it was found that it had an indirect effect on the quality of life by increasing mental health problems such as anxiety and depression, the indirect effect was mostly on anxiety.