Bipolar disorder (BD) is a chronic condition characterized by severe mood swings alternating between episodes of mania and depression. Evidence indicates that protein kinase C (PKC) and oxidative stress are important therapeutic targets for BD. However, what PKC isoforms that are precisely involved in this effect are unknown. Therefore, we evaluated the effects of the intracerebroventricular (ICV) injection of PKC inhibitors (lithium (Li), tamoxifen (TMX), PKCα inhibitor (iPKCα), PKCγ inhibitor (iPKCγ), and PKCε inhibitor (iPKCε)) on the manic-like behaviors and oxidative stress parameters (4-hydroxy-2-nonenal (4-HNE), 8-isoprostane (8-ISO), carbonyl groups, 3-nitrotyrosine (3-NT), glutathione peroxidase (GPx) and glutathione reductase (GR)) in the brains of rats submitted to the model of mania induced by methamphetamine (m-AMPH). Animals received a single ICV infusion of artificial cerebrospinal fluid, Li, TMX, iPKCα, iPKCγ or iPKCε followed by an intraperitoneal injection of saline or m-AMPH before the behavioral analysis (open-field task). Oxidative stress was evaluated in the striatum, frontal cortex, and hippocampus. ICV injection of Li, TMX or iPKCε blocked the m-AMPH-induced increase in the manic-like behaviors - crossings, rearings, visits to the center, sniffing, and grooming. ICV infusion of iPKCα triggered a decrease in these behaviors induced by m-AMPH. Besides, the iPKCε administration significantly prevented the oxidative damage to lipids and proteins, as well as disturbances in the activity of antioxidant enzymes induced by m-AMPH. The findings of the present study suggest that PKCε isoform is strongly implied in the antimanic and antioxidant effects of Li, TMX, and the other PKC inhibitors in the model of mania.