Leptomeningeal seeding is a strong negative prognostic factor for medulloblastoma (MB). The mechanism of leptomeningeal seeding is unclear but may involve epigenetic regulation. In this study, we evaluated the feasibility of a histone deacetylase (HDAC) inhibitor, panobinostat, in the suppression of MB leptomeningeal seeding. Panobinostat decreased the cell viability and proliferation, inducing cell cycle arrest and apoptosis in MB cell lines. The migration and adhesion capabilities were significantly decreased. Panobinostat effectively down-regulated protein expression of CCND1 and ID3 which has been associated with leptomeningeal seeding of MB. After panobinostat treatment, neurophil-like cellular processes developed and expression of synaptophysin and NeuroD1 was increased, indicating neuronal differentiation. In MB leptomeningeal seeding model, the panobinostat-treated group showed significantly decreased spinal leptomeningeal seeding and a survival benefit. The findings demonstrate that panobinostat suppresses MB leptomeningeal seeding through the down-regulation of ID3 and the induction of neuronal differentiation. An HDAC inhibitor might be a potent treatment option for the treatment of MB patients with leptomeningeal seeding.