The present invention relates to a composition for prevention or treatment of ischemic brain disease, comprising, as an effective ingredient, an active form of human Ras homolog enriched in brain (hRheb) (S16H) protein or a nucleic acid coding the protein. The active form of hRheb (S16H) according to the present invention is derived to have constitutive activity through introduction of point mutation into a wild type hRheb gene, is excellent in brain tissue protection and regeneration in an animal model having ischemic brain damage, and thus can be usefully used in prevention, improvement and treatment of ischemic brain disease, including ischemic stroke.