Objective To explore the quality of life and its influencing factors in epilepsy patients with depression. Methods A total of 87 epilepsy patients who were treated in the outpatient or ward of Suzhou Hospital Affiliated to Nanjing Medical University from Mar. 2017 to Feb. 2021 were selected. The quality of life in epilepsy-31 (QOLIE-31), Hamilton depression rating scale-17 (HAMD-17), patient health questionnaire-15 (PHQ-15), and Hamilton anxiety rating scale (HAMA) were used to evaluate the patients’ quality of life, depression, number and severity of somatic symptoms, and anxiety. According to the HAMD-17 score, the patients were divided into depression group (＞17, n＝34) and control (no depression or possible depression) group (≤17, n＝53), the general information and scale scores of the 2 groups of patients were compared. Spearman rank correlation, Pearson correlation and multiple linear regression analyses were used to explore the influencing factors of quality of life in epilepsy patients with depression. Results Compared with the control group, the depression group had a higher proportion of females, more frequent seizures, longer period of worrying episodes, lower satisfaction with treatment, higher PHQ-15 and HAMA scores, and lower total QOLIE-31 score and scores of worry about seizures, emotional health, energy/fatigue and overall quality of life (all P＜0.05). Correlation analysis showed that the quality of life of epilepsy patients with depression was negatively correlated with the severity of depression and anxiety, and the number and severity of somatic symptoms (all P＜0.01). Multiple linear regression analysis showed that the severity of depression and the number and severity of somatic symptoms had impacts on the quality of life of epilepsy patients with depression, explaining 65.4% of the total variation in quality of life (adjusted R²＝0.654, P＜0.01). Conclusion The severity of depression and the number and severity of somatic symptoms are important factors for the impairment of quality of life in epilepsy patients with depression, and effective intervention may improve the quality of life of these patients.