BACKGROUND: One of the leading factors complicating social adaptation after ischemic stroke is cognitive and motor impairment. AIM: This study aimed to evaluate the effect of rehabilitation using virtual reality technologies and the influence of the main clinical and functional parameters on virtual reality (VR) therapy in patients with different degrees of cognitive decline in the acute period of ischemic stroke. MATERIALS AND METHODS: This study examined 170 patients diagnosed with ischemic stroke with cognitive decline according to the Montreal Cognitive Assessment. Depending on the volume of therapy, the patients were divided into two groups: group 1 included 120 patients who received additional therapy using VR technologies (62 patients with moderate cognitive impairment, 58 patients with dementia), and group 2 consisted of 50 patients who received only basic therapy and standard methods of early rehabilitation. In group 1, on days 4–5 following basic therapy, rehabilitation using VR was performed. The Barthel Index (BI) scale, Rankin Scale (mRS), and National Institute of Health Stroke Scale (NIHSS) were used to examine cognitive and functional status, and tests were performed to assess cognitive functions, as well as neuroimaging scales ASPECTS, STRIVE, and MTA. The effectiveness of rehabilitation (ΔRE) was measured by the indicator of changes in the parameters of the VR system before and after treatment. RESULTS: A more significant improvement of the patient’s independence and regression of perceptual and executive functions was demonstrated in group 1 than in the control group. In patients with MCI, significant improvement was observed in all cognitive and functional parameters except semantic information processing, attention, and constructive praxis. In patients with dementia, improvement was noted in NIHSS, speech and amnestic disorders. In group 1, ΔRE was found to be associated with the parameters of perception, attention, semantic information processing, IQCODE, and NIHSS and the presence of hypertension and repeated stroke. In patients with MCI, ΔRE was correlated with lesion size, attention level, BI, mRS, and NIHSS and with age, sex, degree of IQCODE and STRIVE, semantic aphasia, and perceptual impairment in patients with dementia. CONCLUSION: The present study revealed a polymorphism of factors influencing the effectiveness of VR therapy in patients with varying degrees of cognitive decline. Modern approaches to VR rehabilitation of patients with post-stroke cognitive impairment require the development of individual methods of rehabilitation using immersion environment focused on the structure, etiology, and severity of cognitive deficit considering the degree of the patient’s functional state.