Background: Depression, the most common psychiatry comorbidity in patients with epilepsy is common among women, especially those of reproductive age. Although it could be said that the female gender is a risk factor for depression, the risk of inter-ictal depression and its impact on the quality of life (QoL) of women with epilepsy (WWE) has not been sufficiently studied among Nigerians. Materials and Methods: In this cross-sectional case–control study, data were collected from 70 women (29 WWE and 41 women without epilepsy) within the age range ≥18 and ≤55 between July 2010 and March 2011. A questionnaire that includes items-related to demographic information, becks depression inventory-II (BDI-II) and QoL inventory in epilepsy-31 was used for data collection. Result: WWE had a significantly higher BDI-II score (P = 0.001). The frequency of depression was 37.9% in WWE and 4.9% among controls. (Odds ratio 11.9). WWE had poorer QoL score than the control (P ≤ 0.001). Depressed WWE had poorer total QoL (P = 0.007) as well as poorer emotional well-being (<0.001) and social function (P = 0.004) compared with women without epilepsy. Conclusion: Depression is prevalent in this sample of Nigerian WWE of childbearing age with significant impact on their total QoL, emotional well-being and social function. Regular screening for depression among this population of PWE is imperative. Rational drug management as well as non-pharmacological treatment of depressed WWE is emphasized.