Background: Oxidative stress has a significant influence in the initiation and progression of epileptic seizures. It was reported that inhibiting oxidative stress could protect against epilepsy. The aim of the current research is to estimate some biomarkers that reflect the oxidative stress in epileptics, its relation to seizure control as well as to study the impact of antiepileptic drugs (AEDs) on these biomarkers. This case–control study included 62 epileptic patients beside 62 age and gender-matched healthy controls. The epileptic patients subjected to detailed history taking with special regards to disease duration, seizure frequency, and the current AEDs. Laboratory evaluation of serum malondialdehyde (a lipid peroxidation byproduct) and superoxide dismutase (an endogenous antioxidant) were done. Results: Malondialdehyde (MDA) was significantly higher, and superoxide dismutase (SOD) was lower in epileptic patients than in the controls (p < 0.001). Seizure frequency was directly correlated with MDA (r = 0.584, p < 0.001) while inversely correlated with SOD (r = − 0.432, p = 0.008). High MDA and low SOD were recorded in epileptic patients receiving polytherapy as compared to monotherapy (p < 0.001). Conclusions: Epileptic patients had higher oxidative stress biomarkers than healthy individuals. Frequent seizures, long disease duration, and AEDs were associated with higher MDA and lower SOD that reflects an imbalance in the oxidant–antioxidant status among these patients