High-risk neuroblastoma presents a serious clinical challenge with survival rates below 50%. Disease relapse most commonly occurs at distant metastatic sites and remains the primary driver of poor outcomes, emphasizing the need for therapies to target drivers of relapse. This study identified DNA-PKcs as a critical determinant of poor survival and metastatic relapse in neuroblastoma patients. We evaluated which therapeutic modality-chemotherapy or radiotherapy-when combined with DNA-PKcs inhibition, more effectively reduces metastatic burden and prevents recurrence. Colony-forming assays revealed that established neuroblastoma colonies resist doxorubicin alone and require high-dose doxorubicin paired with DNA-PKcs inhibition to suppress progression. In contrast, low-dose radiotherapy in combination with DNA-PKcs inhibition effectively controlled colony progression. Maximal synergy between radiotherapy and DNA-PKcs inhibition was achieved when the inhibitor was administered within 4h post-irradiation. Chronic co-exposure to doxorubicin and peposertib encouraged emergence of therapy-resistant cells, whereas chronic co-exposure to radiotherapy combined with peposertib disrupted neuroblastoma cells self-renewal and prevented long-term colony maintenance. In neuroblastoma metastases, adding DNA-PKcs inhibition to doxorubicin improved efficacy but induced gastrointestinal side effects and failed to eradicate tumors; pairing it with low-dose, fractionated radiotherapy resulted in total lesion regression, impaired tumor self-renewal, and prevented systemic adverse effects. Our findings correlate elevated DNA-PKcs levels with poor patient prognosis and show that low-dose radiotherapy combined with peposertib effectively abrogates neuroblastoma self-renewal compared to chemotherapy-based regimens, thereby implicating DNA-PKcs as a key mediator of metastatic relapse and supporting radiotherapy plus DNA-PKcs inhibition as a compelling therapeutic strategy for relapsed or refractory high-risk neuroblastoma.