Medulloblastoma (MB) is the most prevalent malignant brain tumor in children, exhibiting clinical and genomic heterogeneity. Of the four major subgroups, Group 3 tumors (MYC-MB), display high levels of MYC and metastasis rates. Despite treatment with surgery, radiation, and chemotherapy, patients with Group 3 MB are more likely to develop aggressive recurrent tumors with poor survival. To examine resistance mechanisms, single nuclei multiome analysis of matched primary and recurrent tumors was performed in this study. A persistent progenitor population supporting resistance to therapy was identified. Additionally, distinct chromatin landscapes are linked to altered transcription and correspond to metabolic reprogramming. In vivo modeling of radiation resistance resolves similar chromatin-based metabolic reprogramming focused on wild-type isocitrate dehydrogenase (IDH1) activity. IDH1 inhibition reverses resistance-mediated chromatin changes and enables radiation re-sensitization. Ultimately, these findings demonstrate the efficacy of single-cell multiome analysis in elucidating resistance mechanisms and identifying novel target pathways for MYC-driven medulloblastoma.