Baicalein (BA), a plant-derived active flavonoid in the root of Scutellaria baicalensis, has been widely used to treat stress-related neuropsychiatric disorders, including depression- and anxiety-like behavior. The neurochemical and molecular biological basis of BA on depression-like behavior remains unclear. In the present study, mice received 10, 20, or 40 mg/kg BA (i.p.) 30 min prior to daily exposure to repeated unpredictable stress for 20 days. The tail suspension and forced swimming tests (TST and FST),novelty suppressed feeding and sucrose preference tests (NSFT and SPT) were used for examining the effects of BA on chronic stress-induced depression- and anxiety-like behavior. The results suggested that BA significantly decreased the duration of immobility in both the FST and TST, increased sucrose consumption and decreased latency to feed, which reflect its antidepressant- and anxiolytic-like effects. Furthermore, BA increased the serotonin and dopamine concentrations, and inhibited MAO activity in the hippocampus and cortex of stressed mice. The subsequent cAMP levels and brain derived neurotrophic factor (BDNF) mRNA expression were also increased in these brain regions after treatment with BA. These findings indicate that BA protects mice against chronic stress-induced depression- and anxiety-like behavior possibly by increasing monoamines levels via inhibition of MAO activity, stimulation of cAMP and BDNF expression in the brain regions that are related to emotional disorders. BA may be a valuable agent for treating or alleviating the complex symptoms associated with depression and anxiety.