Chronic mild stress (CMS) is suggested to produce abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamus-pituitary-thyroid (HPT) axis. Therefore, compound that attenuates the neuroendocrinological alterations may have potential as antidepressant. The behavioral and neuroendocrinological effects of icariin, a major constituent of flavonoids isolated from Epimedium brevicornum, were investigated in the CMS model of depression in male Wistar rats. CMS procedure caused an anhedonic state in rats resulted in increased corticotropin-releasing factor (CRF) concentrations in dissected brain regions and serum, decreased total triiodothyronine (tT3) in serum with no significant changes in serum adrenocorticotrophic hormone (ACTH) and thyroxine (tT4). Administration of icariin reversed CMS-induced sucrose intake reduction and CRF elevation. These results suggested that icariin possessed potent antidepressant-like activities which were at least in part mediated by improving the abnormalities in the HPA axis functions. However, we did not find a clear correlation between the HPT axis and icariin treatment in the CMS-treated rats.