: Post-stroke depression (PSD) is a prevalent complex psychiatric disorder that causes delay to functional recovery from rehabilitation and also increases cognitive impairment. The etiology of PSD remains controversial and appears to be physical and psycho-social in origin, alone or in combination. The causes of PSD as well as the mechanisms conferring beneficial antidepressant effects in the context of ischemic brain injury are still unknown. In addition, appropriate treatment strategies for therapy to prevent stroke-induced depression-like behavior remain to be developed. This paper, therefore, proposes two hypotheses for post-stroke depression: The inflammatory hypothesis, which is the increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas causing the pathogenesis of post-stroke depression and the glutamate hypothesis, where the excess glucocorticoids released from stress-induced over-activation of hypothalamus-pituitary-adrenal (HPA) lead to dysfunction of glutamatergic transmission. Neurotrophins, especially brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) both play various roles in the central nervous system (CNS), attenuate apoptosis in cultured neurons, stimulate neurogenesis and increase survival and protect neuronal tissues from cell death induced by ischemia or depression. We also touch upon recent treatment strategies including inhibition of pro-inflammatory cytokines, SSRI, neurotrophins and cell-based therapies. In the present review, we provide an overview of recent evidence concerning the mechanisms of post-stroke depression and propose four prospective treatment strategies so as to provide references for clinical evidence-based medications.