In this paper, the anti-depressant effects of Acanthopanax senticosus extract (ASE) were studied using animal models of depression including the forced swimming and tail suspension tests. The anti-depressive mechanism of ASE was explored by monitoring the levels of monoamine neurotransmitters including 5-hydroxytrylamine (5-HT), norepinephrine (NE), and dopamine (DA), as well as cAMP response element-binding (CREB) protein expression in the whole brain of mice following the tail suspension test. Our results showed that intragastric administration of ASE at a dose of 2000 mg/kg for seven days significantly reduced the duration of immobility in both the forced swimming test and the tail suspension test. These results indicate that ASE possesses antidepressant-like properties. Pre-treatment with 2000 mg/kg of ASE for seven days significantly elevated the levels of 5-HT, NE, and DA in the whole brain of mice. Moreover, ASE at doses of 1000 and 2000 mg/kg significantly up-regulated the level of CREB protein. Taken together, these findings suggest that the anti-depressive mechanism of ASE may be mediated via the central monoaminergic neurotransmitter system and CREB protein expression. Therefore, administration of ASE may be beneficial for patients with depressive disorders. Copyright © 2013 John Wiley & Sons, Ltd.