Severe brain damage by trauma, ischemia, and hemorrhage lead to fatal conditions including sudden death, subsequent complications of the extremities and cognitive dysfunctions. Despite the urgent need for treatments for these complications, currently available therapeutic drugs are limited. Blood–brain barrier (BBB) disruption is a common pathogenic feature in many types of brain damage. The characteristic pathophysiological conditions caused by BBB disruption are brain edema resulting from an excessive increase of brain water content, inflammatory damage caused by infiltrating immune cells, and hemorrhage caused by the breakdown of microvessel structures. Because these pathogenic features induced by BBB disruption cause fatal conditions, their improvement is a desirable strategy. Many studies using experimental animal models have focused on molecules involved in BBB disruption, including vascular endothelial growth factors (VEGFs), matrix metalloproteinases (MMPs) and endothelins (ETs). The inhibition of these factors in several experimental animals was protective against BBB disruption caused by several types of brain damage, and ameliorated brain edema, inflammatory damage, and hemorrhagic transformation. In patients with brain damage, the up-regulation of these factors was observed and was related to brain damage severity. Thus, BBB protection by targeting VEGFs, MMPs, and ETs might be a novel strategy for the treatment of brain damage.