Metastatic Group 3 medulloblastoma (G3 MB) have been shown in several studies to be very high risk, particularly those harboring MYC amplification. More effective therapies are especially important for these patients. CUDC-907, a novel dual inhibitor targeting the MYC upstream pathway (HDAC/PI3K), shows significant antitumor efficacy across multiple cancer types. However, the antitumor effects and underlying mechanisms of CUDC-907 in MB, particularly in very high-risk MB, remain unexplored. In this study, we showed that MYC amplified G3 MB cells, patient-derived organoids and xenograft models were sensitive to CUDC-907. CUDC-907 inhibited MYC expression through the HDAC and PI3K pathways, and then induced G0/G1 phase arrest through the MYC-P21/P27-CDKs/cyclins axis. Furthermore, when CUDC-907 was combined with chemotherapeutic drug cisplatin, G0/G1 phase blocking effect was further enhanced. CUDC-907 in combination with radiotherapy (RT) inhibited DNA damage repair and increased DNA damage. These findings indicate that CUDC-907, either as a monotherapy or in combination with chemoradiotherapy, represents a promising therapeutic strategy for MYC amplified G3 MB, potentially influencing future clinical trials targeting this patient population.