Objective To study the effect of Areca catechu L. on depression-like behavior in mice and its mechanism. Methods Behavioral despair and reserpine antagonism models were established. Male ICR mice were divided into Areca catechu L. low, medium and high dose groups ( 160, 320 and 640 mg / kg) and a positive control group (fluoxetine, 20 mg / kg). Administration was performed by continuous gavage for 14 days. The antidepressant activity of Areca catechu L. was evaluated by the behavioral test of open field test, tail suspension test and forced swimming test. The antidepressant effect of Areca catechu L. was also evaluated by the reserpine antagonism test to evaluate the effect of Areca catechu L. on monoaminergic nervous system functions and the change of oxidative stress level. The content of neurotransmitters in mice was determined by LC-MS / MS analysis. The anti-oxidative stress effect of Areca catechu L. was assessed by measuring superoxide dismutase (SOD), malondialdehyde (MDA) and catalase (CAT). Results There were no significant differences in body weight between the groups. The open field text showed that Areca catechu L. had no effect on the locomotor activity of mice. The medium and high dose groups of Areca catechu L. had significantly reduced time in the tail suspension test (P<0.05), and the low and high dose groups of Areca catechu L. had significantly reduced immobility time of mice in the forced swimming test (P<0.05). In the reserpine antagonism test, compared with the model group, the low and high dose groups of Areca catechu L. had antagonized eyelid ptosis induced by reserpine (P<0.05), and the three doses significantly antagonized the decrease of body temperature induced by reserpine (P<0.01). Compared with reserpine antagonism model group, the 5-HT content in the brain tissue of mice in the Areca catechu L. high dose group (P<0.01), DA content in Areca catechu L. low and high dose groups (P<0.01), and the GABA level in the Areca catechu L. low- and medium-dose groups (P<0.05) were significantly increased and the 5-HIAA level in Areca catechu L. medium and high dose groups was decreased significantly (P<0.01). SOD and CAT levels were significantly increased (P<0.01, P< 0. 01) in the three dose groups of Areca catechu L.. MDA content was significantly decreased (P<0.01) in the medium and high dose groups of Areca catechu L.. Conclusions Areca catechu L. has good anti-depressant efficacy in stress despair and reserpine antagonistic drug models without affecting motor activity or body weight. Its anti-depressant mechanism of action may be related to enhancement of monoamine neurogenic system levels and anti-oxidative stress effects.