The migration of vascular smooth muscle cells (VSMCs) is found to participate in vascular remodeling which is pivotal in the pathogenesis of vascular diseases, for instance atherosclerosis and restenosis. However, the underlying mechanisms of how mechanical strain influence VSMC migration remain to be elucidated. Histone deacetylases (HDACs) are involved in chromatin remodeling and modification of both histone and nonhistone transcription regulatory proteins, thus HDACs modulate genes important for complex biological processes. But whether HDACs take part in modulating migration of VSMCs induced by mechanical strain is poorly understood. Here, we showed that cyclic strain of 1 Hz at 10% elongation for 48 h significantly inhibited the migration of cultured VSMCs compared to the static one. The cyclic strain upregulated the levels of acetylased histone H3 and HDAC7 while downregulated the level of HDAC3/4 in VSMCs. Furthermore, the mechanically induced VSMC migration was diminished by treatment with tributyrin, a HDAC inhibitor. We also observed hyperacetylation of histone H3 and reduced expression of HDAC7 upon tributyrin treatment. These results provide convincing evidence that HDACs are involved in the migration of VSMCs induced by mechanical strain through chromatin remodeling. Thus, inhibition of HDAC may be beneficial in preventing the migration of VSMCs in treating proliferative vascular diseases.