Stress is a significant factor in the etiology of depression. Stellate ganglion block (SGB) has been shown to maintain the stability of the autonomic system and to affect the neuroendocrine system, including the hypothalamic-pituitary-adrenal (HPA) axis. The objective of this study was to determine the antidepressant-like effects of SGB on the autonomic system and the HPA axis, apoptosis-related proteins, related spatial learning and memory impairment, and sensorimotor dysfunction.Forty-eight Sprague Dawley rats were assigned to four experimental groups: control + saline (sham group), control + SGB (SGB group), unpredictable chronic mild stress (UCMS) + saline (UCMS group), and UCMS + SGB (UCSG group). Stress-induced effects and the function of SGB were assessed using measures of body weight, coat state, sucrose consumption, and behavior in open-field and Y-maze tests. Neuronal damage was assessed histologically using the hematoxylin-eosin (HE) staining method, while western blotting was used to investigate changes in the expression of apoptosis-related proteins. Plasma corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), corticosterone (CORT), noradrenaline and adrenaline were measured to evaluate changes in the autonomic system and HPA axis.SGB treatment significantly improved sensorimotor dysfunction and spatial learning and memory impairment following UCMS. Moreover, UCMS significantly decreased body weight, sucrose preference and anti-apoptotic protein Bcl-2, and increased scores on measures of coat state, adrenal gland weight, levels of CORT, CRF, ACTH, noradrenaline and adrenaline, as well as increased neuronal loss, cell shrinkage, nuclear condensation, and the pro-apoptotic protein Bax. These symptoms were attenuated by treatment with SGB.These findings suggest that SGB can attenuate depression-like behaviors induced by chronic stress. These protective effects appear to be due to an anti-apoptotic mechanism of two stress pathways-the autonomic system and the HPA axis.