There has been a growing body of evidence indicating that the oxytocin (OT) system plays a significant role in the neurophysiology of chronic stress-related mood disorders in recent years. However, the precise alterations for the OT system in response to chronic stress and the underlying mechanism remains unclear. The present study demonstrated that chronic unpredictable stress (CUS) resulted in a reduction in the expression of RAGE and OTR, as well as an inhibition of AP-1 phosphorylation. RAGE knockdown in hippocampus DG induced depressive-like behaviors, down-regulated the OTR protein and mRNA levels, and reduced the AP-1 phosphorylation. The administration of OT via the nasal route reversed the depressive-like behaviors induced by RAGE knockdown, increased the levels of BDNF expression and AP-1 phosphorylation. On the other hand, RAGE over-expression in the hippocampus DG resisted the effects of CUS on depression-like behaviors, AP-1 phosphorylation, and OTR expression. These finding suggested that RAGE signaling pathway is involved in CUS induced depressive-like behaviors at least partially by regulating OTR expression.