We modeled the common clinical conditions of human stroke in fully conscious rats through an occlusion of the middle cerebral artery (MCAO) by means of unilateral microinjection of Endothelin-1 (ET1) in the vicinity of the artery (EMCAO model). Since the role of serotonin (5-HT) system in the regulation of the cerebral blood flow has been known for long time and no data are available at present for the effects of 5-HT antagonists in focal ischemia models, we further tested whether a blockade of the serotonin-2A (5-HT2A) receptors by ketanserin (20 min post-ET1) would diminish the late EMCAO-induced functional and morphological changes. The long-term neurological (postural reflex) and electroencephalogram (EEG) changes in the somatosensory cortical region (S1FL) were used to assess the effects of ketanserin on the post-ischemic changes. The study was supplemented by a histopathological examination of S1FL area and striatum of both hemispheres. The EMCAO/ ketanserin-treated rats showed much smaller neurological deficits than the EMCAO rats treated with vehicle. This effect was observed on day 3 and lasted until the end of experiments-14 days after EMCAO. The depression of alpha and beta EEG frequencies found after EMCAO was significantly and earlier restored following ketanserin. Notably, there was not augmentation of the pathological slow EEG waves at day 3 post-ET1 in the EMCAO ketanserin-treated rats compared with that observed in the EMCAO vehicle-treated rats. Although there were mild morphological changes in the penumbral S1FL cortical region after EMCAO, ketanserin reduced the histopathological difference between the ipsilateral and contralateral cortical S1FL regions, but did not change the difference between striatum of both sides. Ketanserin reduced the infarct size in ipsilateral hemisphere (mainly cortex). In conclusion, the results showed that treatment with ketanserin at the early stage of stroke may reduce the consequences of ischemia by improvement of functional and morphological recovery at later stages. Ketanserin appears to be a promising candidate for mitigating the consequences of stroke.