Growing evidence indicates that an increase of orexin (or hypocretin) signaling is involved in the pathophysiology of major depression, but little is known regarding the causal link between the orexinergic system and depressive-like states. Here we blocked orexin receptors in mice subjected to unpredictable chronic mild stress (UCMS) to investigate putative antidepressant-like effects of this treatment, as well as the underlying mechanisms. BALB/c mice were exposed to 9 weeks of UCMS and from the third week onward treated daily with fluoxetine (20 mg/kg per day, per os) or with the dual orexin receptor antagonist almorexant (100 mg/kg per day, per os). The effects of UCMS regimen and pharmacological treatments were assessed by physical measures and behavioral testing. The dexamethasone suppression test was performed to examine the integrity of the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, and immunohistochemical markers were used to assess cell proliferation (Ki-67), immature newborn neurons (doublecortin), and mature newborn neurons (5-bromo-2'-deoxyuridine/NeuN) in the dorsal and ventral parts of the hippocampus. Our results show that 7 weeks of fluoxetine or almorexant treatments counteract the UCMS-induced physical and behavioral alterations. Both treatments prevented the HPA axis dysregulation caused by UCMS, but only fluoxetine reversed the UCMS-induced decrease of hippocampal cell proliferation and neurogenesis, while chronic almorexant treatment decreased cell proliferation and neurogenesis specifically in the ventral hippocampus. Taken together, this is the first evidence that pharmacological blockade of the orexinergic system induces a robust antidepressant-like effect and the restoration of stress-related HPA axis defect independently from a neurogenic action.