Exposure to chronic stress in rodents and psychosocial stress in humans has been shown to alter cognitive functions and has been linked to the pathophysiology of mood disorders. The purpose of the present study was to investigate effects and possible mechanisms of a chronic mild stress (CMS) procedure on cognitive behaviors in Swiss albino mice using the object recognition test (ORT) and object location test (OLT). Results showed that CMS exposure impaired cognitive performance and produced amnesia of acquired information in both ORT and OLT. Furthermore, the cognitive impairment was coexistent with increased plasma levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), as well as with enhanced plasma levels of corticosterone (CORT), corticotrophin-releasing hormone (CRH) and adrenocorticotrophic hormone (ACTH). In addition, severe neuronal cell damage was found, as bromodeoxyuridine (BrdU) positive cells and the expression of brain derived neurotrophic factor (BDNF) in dentate gyrus (DG) of hippocampus were decreased after 5 weeks CMS procedure. Taken together, these findings indicated that CMS exposure-induced impairment of cognitive behaviors might be attributed to the stress-related alterations in brain homeostasis that were reflected in changes in the neuroimmune and neuroendocrine systems as well as in neurogenesis.