A bioactive compound from Paecilomyces tenuipes (BCPT) has an inhibitory effect on monoamine oxidase A (MAO-A) in vitro. Researchers have thought that BCPT may be a potential antidepressant. The MAO-A suppressor moclobemide served as a control, and this study investigated the mechanisms of BCPT as an antidepressant. Results demonstrated that BCPT induced significantly increased sucrose intake in chronic unpredictable stressed rats, shortened immobility time in forced swimming mice, improved the scores of blepharoptosis and akinesia in reserpine-treated mice, increased the number of 5-hydroxy tryptophan-induced head-twitches, remarkably enhanced the expression of hippocampus mineralcorticoid receptor and glucocorticoid receptor mRNA, decreased the ratio of mineralcorticoid receptor to glucocorticoid receptor and raised the levels of dopamine, norepinephrine and 5-hydroxytryptamine, while decreasing hydroxyindole acetic acid levels or dihydroxy-phenyl acetic acid in chronic unpredictable stressed rats. Behavioral test results suggested that BCPT potentially had antidepressant-like activity. Meanwhile, BCPT increased the levels of neurotransmitters, and mineralcorticoid receptor and glucocorticoid receptor mRNA in the hippocampus, which may be an important mechanism of its antidepressant effect. The bioactive compound from Paecilomyces tenuipes (BCPT) has an inhibitory effect on monoamine oxidase A (MAO-A) in vitro. Researchers have thought that BCPT may be a potential antidepressant. The MAO-A suppressor moclobemide served as a control, and this study investigated the mechanisms of BCPT as an antidepressant. Results BCPT induced significantly increased sucrose intake in chronic unpredictable stressed rats, shortened immobility time in forced swimming mice, improved the scores of blepharoptosis and akinesia in reserpine-treated mice, increased the number of 5 -hydroxy tryptophan-induced head-twitches, remarkably enhanced the expression of hippocampus mineralcorticoid receptor and glucocorticoid receptor mRNA, decreased the ratio of mineralcorticoid receptor to raised levels of dopamine, norepinephrine and 5-hydroxytryptamine, while decreasing hydroxyindole acetic acid levels or dihydroxy-phenyl acetic acid in chronic unpredictable stressed rats. Behavioral test results suggested that BCPT had had antidepressant-like activity. Meanwhile, BCPT increased the levels of neurotransmitters, and mineralcorticoid receptor and glucocorticoid receptor mRNA in the hippocampus, which may be an important mechanism of its antidepressant effect.