In this study, we assessed oxidative stress parameters in rats submitted to an animal model of mania induced by ouabain (OB) which included the use of lithium (Li) and valproate (VPA). In the reversal treatment, animals received a single ICV injection of OUA or cerebrospinal fluid (aCSF). From the day following the injection, the rats were treated for 6 days with intraperitoneal injections of saline (SAL), Li or VPA twice a day. In the prevention treatment, the rats received intraperitoneal injections of Li, VPA, or SAL twice a day for 12 days. In the 7th day of treatment the animals received a single ICV injection of either OB or aCSF. Locomotor activity was measured by open-field test and oxidative stress parameters were measured in rat hippocampus and prefrontal cortex. Li and VPA reversed OB-related hyperactive behavior in the open-field test in both experiments. In addiction, we observed that OB induced oxidative damage in the total tissue and in submitochondrial particles of prefrontal and hippocampus. Li and VPA treatment reversed and prevented the OB-induced damage in these structures, however this effect varies depending on the brain region and treatment regime. Moreover, the activity of the antioxidants enzymes superoxide dismutase (SOD) and catalase (CAT) was increased and decreased, respectively, in the brain of OB-administered rats. Li and VPA increased SOD and CAT in rats OB-subjected in both experimental models. These findings suggest a relationship between OB-induced hyperactivity and oxidative stress in the brain and an important role of oxidative stress in mania.