Background: Post-stroke depression (PSD) is the most frequent psychiatric complication following ischemic stroke. It affects up to 60% of all patients and is associated with increased morbidity and mortality following ischemic stroke. The pathophysiology of PSD remains elusive and appears to be multifactorial, rather than “purely” biological or psychosocial in origin. Thus, valid animal models of PSD would contribute to the study of the etiology (and treatment) of this disorder. Methods: The present study depicts a rat model for PSD, using middle cerebral artery occlusion (MCAO). The two-way shuttle avoidance task, Porsolt forced-swim test, and sucrose preference test were employed to assess any depression-like behavior. Localized brain expressions of brain-derived neurotrophic factor (BDNF) protein levels were evaluated to examine the possible involvement of the brain neuronal plasticity in the observed behavioral syndrome. The raw data were subjected to unsupervised fuzzy clustering (UFC) algorithms to assess the sensitivity of bio-behavioral measures indicative of depressive symptoms post MCAO. Results: About 56% of the rats developed significant depressive-like behavioral disruptions as a result of MCAO compared with 4% in the sham-operated control rats. A pattern of a depressive-like behavioral response was common to all affected MCAO animals, characterized by significantly more escape failures and reduced number of total avoidance shuttles, a significant elevation in immobility duration, and reduced sucrose preference. Significant downregulations of BDNF protein levels in the hippocampal sub-regions, frontal cortex, and hypothalamus were observed in all affected MCAO animals. Conclusion: The UFC analysis supports the behavioral analysis and thus, lends validity to our results.