Medulloblastoma and pineoblastoma are malignant childhood brain tumours where many patients don’t respond to existing therapy, highlighting the need for new therapeutic strategies. Utilising a high-throughput drug screening approach we sought to identify additional effective chemotherapeutics with the aim to repurpose drugs already used to treat other diseases for the treatment of these paediatric cancers. Repurposed drugs have the advantage of having well-characterised pharmacokinetic profiles and toxicities, enabling rapid translation into the clinic. To identify compounds that inhibit the growth of multiple cell lines derived from pineoblastoma and medulloblastoma, we have screened 3162 FDA-approved drugs and other bioactive compounds using an alamar blue based redox assay. We have identified 38 and 50 compounds that have sub-micromolar effective doses against pineoblastoma and medulloblastoma cell lines, respectively. Effective compounds have diverse mechanisms of action compared to the current drugs used in the clinic and approximately 50% of compounds were known or predicted to cross the BBB by computational algorithms. To evaluate the efficacy of potential new drugs, a selection have been tested as single agents and in combination with conventional chemotherapeutics (vincristine, cisplatin and cyclophosphamide) in multiple medulloblastoma and pineoblastoma cell lines. Drug combinations demonstrating synergistic interactions in vitro are currently being examined for efficacy in vivo using orthotopic xenograft mouse models. This study employs a comprehensive drug discovery pipeline enabling the thorough assessment of novel drugs for paediatric brain tumour treatment, enabling the exclusion of potentially ineffective treatments and prioritisation of truly beneficial new treatments for clinical trial.