Acute central nervous system (CNS) injuries, including stroke, traumatic brain injury (TBI), and spinal cord injury (SCI), are common causes of human disabilities and deaths, but the pathophysiology of these diseases is not fully elucidated and, thus, effective pharmacotherapies are still lacking. Valproic acid (VPA), an inhibitor of histone deacetylation, is mainly used to treat epilepsy and bipolar disorder with few complications. Recently, the neuroprotective effects of VPA have been demonstrated in several models of acute CNS injuries, such as stroke, TBI, and SCI. VPA protects the brain from injury progression via anti-inflammatory, anti-apoptotic, and neurotrophic effects. In this review, we focus on the emerging neuroprotective properties of VPA and explore the underlying mechanisms. In particular, we discuss several potential related factors in VPA research and present the opportunity to administer VPA as a novel neuropective agent.