Aims: Increases in protein kinase C (PKC) and oxidative stress have been related to mania. Drugs with antioxidant effects or inhibitory actions on PKC may have antimanic effects. The flavonoid quercetin has antioxidant and PKCinhibiting effects that resemble those of lithium, the first-line treatment for mania in bipolar disorder. We hypothesized that quercetin may have antimanic-like effects in an animal model. Main methods: In the present study, we investigated the effects of acute and chronic treatment with quercetin (2.5, 5,10, and 40 mg/kg, i.p.) in male Swiss mice that were subjected to methylphenidate (5 mg/kg, i.p.)-induced hyperlocomotion, an animal model of mania. Lithium (100 mg/kg, i.p.) and diazepam (5 mg/kg, i.p.) were used as positive and negative controls, respectively. We also evaluated the effects of these treatments on methylphenidate-induced oxidative stress in the brain by measuring reduced glutathione (GSH) and lipid peroxidation (LPO) levels in the prefrontal cortex, hippocampus, and striatum. Key findings: Acute and chronic (21-day) treatment with lithium and diazepam reduced methylphenidateinduced hyperlocomotion. Chronic but not acute treatment with quercetin (10 and 40 mg/kg) blocked methylphenidate-induced hyperlocomotion. These effects of lithium and quercetin occurred at doses that did not alter spontaneous locomotor activity, whereas diazepam reduced spontaneous locomotor activity. Chronic treatment with lithium and quercetin blocked the methylphenidate-induced increase in LPO levels in the striatum. Significance: These results suggest that chronic quercetin treatment has antimanic-like and antioxidant effects, thus encouraging further studies of quercetin as a putative new antimanic drug. (C) 2017 Elsevier Inc. All rights reserved.