Objective: Acorus calamus (AC) L. (Araceae) is an annual semi-aquatic and aromatic plant found in Europe, North America and Asia. Its rhizomes are often used by Native Americans, Americans, and Chinese as well as by other cultures. Ethnobotanical studies and documents have shown their use in various disease treatments, such as insomnia, mental disorders, diabetes mellitus, epilepsy, inflamma-tion, asthma, neuropathic pain, and diarrhea. In this study, the antidepressant activity of methanolic and hydroalcoholic extracts of the AC rhizome part in mice was investigated. Methods: Three doses of methanolic extract of AC rhizome (MEACR) (25, 50 and 100 mg/kg b.wt), three doses of hydroalcoholic extract of AC rhizome (HAACR) (100, 200 and 400 mg/kg b.wt), and standards (imipramine, 15 mg/kg b.wt and fluoxetine, 20 mg/kg b.wt) was daily oral administration to the mice for consecutive 14 days. The extract effect on the immobility time was monitored by a tail suspension test (TST) and a forced swimming test (FST). Monoamine oxidase (MAO) levels were also analyzed using standard methods. Results: The optimum antidepressant activity was viewed at 100 mg/kg b.wt of MEACR extract and 400 mg/kg b.wt of HAACR extract with 23.82％ and 20.59％ immobility period reduction, respectively. Besides, the extracts weakened the FST-induced elevation of MAO activity significantly and returned to near-normal levels of neurotransmitters in the brain. 100 mg/kg b.wt or above of MEACR extract significantly prevented the MAO-A and MAO-B activities in mice brain at a dose-dependent fashion. But, just 400 mg/kg b.wt of HAACR extract prevented the activity of MAO-A and MAO-B. Fluoxetine and imipramine showed a tendency to prevent the activity of MAO-A and MAO-B. Conclusion: This study suggests that AC rhizome extract mediated antidepressant activity by modulating the central neurochemical and hypothalamic-pituitary-adrenal (HPA) axis in response to FST and TST-induced stress. Therefore, AC rhizome extract can be used as a valuable plant supplement to treat depressive disorders.