Post-stroke depression is a common neuropsychiatric affective disorder that may develop after a stroke event. In addition to abnormalities in the biogenic amine neurotransmitters and cytokine expression induced by stroke we will focus on the role of oxidative stress and hypothesize that polyphenols may be useful as therapeutics targets for the treatment of post-stroke depression. In this paper, we discuss the hypothesis that increased oxidative stress in cerebral tissues during ischemia is implicated in the pathogenesis of depressive-like symptoms following stroke. There is substantive evidence regarding the role of oxidative stress in the pathogenesis of both stroke and depression, which provides support to this hypothesis. Reactive oxygen species, generated during stroke, cause oxidative stress, lipid peroxidation, protein oxidation, and DNA damage in neural tissues. The resultant pathophysiological processes in the neural tissues could be considered a leading mechanism in the induction of post-stroke depression. Antioxidants including polyphenols therefore, may play an important role in the outcomes of ischemia and stroke, due to their ability to protect neurons against oxidative stress, to mitigate ischemic damage via inhibition of lipid peroxidation and ability to interact with the generation of nitric oxide from the vascular endothelium, and also to decrease inflammation. These data suggest that polyphenols may therefore be a useful new therapeutic target for the treatment of post-stroke depression.