Histone deacetylases (HDACs) play a key role in the homeostasis of histone acetylation and gene transcription. Histone hypoacetylation and transcriptional dysfunction have been identified in a large number of neurological diseases, including ischemic and hemorrhagic stroke. HDAC inhibitors (HDACi) have emerged as a promising therapeutic intervention in neurodegenerative disorders. Here we review and discuss recent observations in the application of the HDACi to combat the effects of stroke in animal and cell culture models. These agents raise histone acetylation levels, adjust the transcription of associated genes, and exert neuroprotective benefits against stroke. Clinical randomized trials should be performed to further investigate the benefits of HDACi for stroke patients.