Neuroblastoma is an aggressive childhood malignancy of the developing sympathetic nervous system. High risk neuroblastoma which has less than 50% survival rates is frequently characterized by MYCN amplification. Elevated MYCN expression in neuroblastoma cells can be maintained by a histone chaperone FACT protein in a feed-forward manner. CBL0137, or curaxin, is a small-molecule FACT inhibitor that destabilises chromatin by interfering with the binding of FACT to DNA. Using a high-penetrant transgenic Th-MYCN mouse model where neuroblastomas develop spontaneously by 7 weeks of age, we have previously shown that CBL0137, alone or combined with chemotherapy, suppressed MYCN expression and significantly extended survival rates. Phase 1 clinical trials are currently in progress, testing CBL0137 in advanced adult cancer. Through a high-throughput drug screen, we have identified that combination of CBL0137 and the FDA-approved HDAC inhibitor panobinostat exerts a strong synergy both in vitro and in vivo in two poor-prognosis childhood cancer models, namely, diffuse intrapontine glioma (DIPG) and MLL-rearranged leukemia. Further testing of this combination in neuroblastoma cells showed that CBL0137 and panobinostat synergistically reduce cell viability and tumour clonogenicity. More strikingly, combination treatment of CBL0137 and panobinostat eradicated all tumours in tumour-bearing Th-MYCN mice, leading to complete regression long-term. Our in vitro mechanistic studies demonstrated that panobinostat markedly enhanced chromatin destabilization induced by CBL0137, resulting in increased loss of histone subunit H1 from chromatin. Moreover, CBL0137 suppressed repair of the DNA damage caused by panobinostat, thereby activating apoptosis. Our studies have identified a highly effective, new drug combination for high-risk paediatric cancers with poor outcomes, and have provided insights into the mechanisms of interaction of CBL0137 and panobinostat, which will greatly facilitate clinical development of efficacious and low toxic therapies for these childhood cancers.