The significance of oxidative stress has been assessed and proven in the etiopathogenesis of many cutaneous disorders, but there are few studies that evaluated the role of only some factors involved in oxidative stress in patients with melasma. This study aimed to examine the role of oxidative stress in melasma and assess the relationship between systemic oxidative stress and the severity and extension of this disease. In this study, the serum levels of superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), malondialdehyde (MDA), protein carbonyl (PC), selenium (Se), vitamin E (vit E), and vitamin C (vit C) of fifty patients with melasma were compared with those of fifty controls. The serum level of MDA was significantly higher in the melasma group (3.08 vs. 2.35 U/mL; p < 0.05), and it was positively correlated with the severity (r = 0.4; p < 0.001) and extension (r = 0.3; p < 0.05) of the disease. Furthermore, the serum level of vit C was significantly lower in melasma patients (2.16 vs. 2.57 μg/mL; p < 0.001). Systemic oxidative stress has a key role in the etiopathogenesis of melasma. Serum concentrations of MDA and vitamin C are indicators of this impairment.