Introduction: Severe acquired brain injury (SABI) is a leading cause of death and disability, and it is defined as a brain injury that occurs after birth due to traumatic or non-traumatic causes. Reality orientation therapy (ROT) uses repeated time–place–person orientation and meaningful stimuli to develop a better understanding of the environment and has great potential as an effective strategy to improve cognitive and behavioral functioning. Objective: This study aims to investigate the feasibility and potential effects of virtual reality orientation therapy (VR-rot) on optimizing cognitive and behavioral functioning and depressive symptoms post-SABI. Method: Forty patients with SABI were enrolled from October 2022 to December 2023 and divided into two groups: the experimental group (EG, n = 20) received VR_rot, while the control group (CG, n = 20) received standard ROT (S_rot). All patients were evaluated with a psychometric battery, including the Mini-Mental State Examination (MMSE) and the Hamilton Rating Scale for Depression (HRS-D), administered before (T0) and after the end (T1) of rehabilitation. Results: Within-group comparisons indicated a statistically significant change in MMSE scores from T0 to T1 in the EG and CG, with the EG showing a greater improvement than the CG. Regarding HRS-D scores, the EG showed a statistically significant change. VR-ROT could be a valuable tool for improving cognitive–behavioral functioning in SABI patients. Conclusions: The VRRS can help reduce depressive symptoms and improve the reality orientation deficit caused by traumatic brain injury and stroke on brain tissue. This study highlights the benefits of virtual reality.