Abstract Despite the overall good outcome of children with medulloblastoma (MB), a subset faces the challenge of highly aggressive metastatic tumors. The poor prognosis for these patients underscores the urgent need for advancing therapeutic approaches. Minnelide, an analog of the natural product triptolide, exhibits potent antitumor activity in preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, Minnelide has not been assessed against MB. Using a bioinformatic dataset integrating cellular drug response and gene expression, we predicted sensitivity of Group 3 (G3) MB, characterized by a poor five-year survival, to triptolide/Minnelide. Subsequent experiments confirmed the ability of both triptolide and Minnelide to reduce the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a crucial driver of G3 MB, as a downstream target of these drugs. We validated the MYC dependency and demonstrated that triptolide affects both MYC transcription and protein stability. Notably, Minnelide acted in vivo on MYC, leading to reduced tumor growth and metastatic spread, resulting in improved survival in mouse and patient-derived G3 MB models. Furthermore, Minnelide enhanced the efficacy of adjuvant chemotherapy, suggesting its potential repurposing for treating MYC-driven G3 MB patients.