Neurosurgical procedures can cause inevitable brain damage resulting from the procedure itself. Unavoidable cortical and parenchymal incisions, intraoperative hemorrhage, brain lobe retraction and thermal injuries from electrocautery can cause brain injuries attributable exclusively to the neurosurgical operations and collectively referred to as surgical brain injury (SBI). This particular brain damage cannot be demarcated from the underlying brain pathology and has not been studied previously. Recently, we developed rat and mouse models to study SBI and the underlying cellular mechanisms. The animal modeling mimics a neurosurgical operation and causes commonly encountered postoperative complications such as brain edema following blood brain barrier (BBB) disruption, and neuronal cell death. Furthermore, the SBI animal model allows screening of known experimental neuroprotective agents and therapeutic agents being tried in clinical trials as possible pretreatments before neurosurgical procedures. In the present review, we elaborate on SBI and its clinical impact, the SBI animal models and their clinical relevance, and the importance of blanket neuroprotection before neurosurgical procedures.