Patients with neuroblastoma associated with MYCN oncogene amplification or LIN28B gene over-expression experience a very poor prognosis. BET bromodomain inhibitors are emerging as one of the most promising novel classes of anticancer agents by blocking the BET bromodomain proteins BRD3 and BRD4 from activating transcription of oncogenes such as MYC and MYCN. However, treatment with BET bromodomain inhibitors alone does not result in cancer remission in many murine models. Here we show that BRD3 and BRD4 directly bound to the LIN28B gene promoter and activated LIN28B gene transcription, that treatment with the BET bromodomain inhibitor JQ1 reduced LIN28B gene expression, and that knocking down LIN28B expression reduced the expression of N-Myc protein, but not N-Myc mRNA. Combination therapy with JQ1 and the histone deacetylase inhibitor panobinostat synergistically induced growth inhibition and apoptosis in neuroblastoma cells, but not normal non-malignant cells. Genome-wide differential gene expression studies showed that JQ1 reduced oncogene expression, that panobinostat activated tumour suppressor gene expression, and that combination of JQ1 and panobinostat synergistically reduced the expression of a large set of genes, predominantly oncogenes including LIN28B but not MYCN. Importantly, JQ1 and panobinostat synergistically and considerably reduced the expression of both LIN28B and N-Myc oncoproteins. In neuroblastoma-bearing mice, JQ1 and panobinostat combination therapy synergistically and considerably reduced LIN28B and N-Myc protein expression in tumor tissues and blocked tumor progression. Our findings have therefore identified a novel strategy to simultaneously reduce LIN28B and N-Myc expression and a novel therapeutic approach for the treatment of aggressive neuroblastoma.