Finding an effective treatment for MYCN amplified (MNA) high-risk neuroblastoma patients represents an open challenge in pediatric oncology. We have recently shown that MYCN upregulates the three components of the MRE11/RAD50/NBS1 (MRN) complex during granule cell progenitors expansion in postnatal cerebellar development to restrain the deleterious effects of MYCN-dependent replication stress. Analysis of multiple datasets in R2, indicated that MRE11 and RAD50 are significantly more expressed in MNA compared to MYCN single copy primary neuroblastomas. Moreover, all MRN components are upregulated in MYCN-dependent medulloblastomas arising in mice with constitutively active Hedgehog pathway. Thus, we tested whether the MRN complex is necessary for proliferation/survival in MNA neuroblastoma. MRE11 or NBS1 RNAi-mediated knock down impaired proliferation and colony formation in a MYCN-dependent way. Pharmacological inhibition of the MRN complex via mirin, a MRE11 exonuclease drug inhibitor, selectively induced cell death in MNA compared to MNSC cells or non-neuroblastoma cancer models. A mirin analog selective for MRE11 exonuclease inhibition, but not an endonuclease specific inhibitor, induced cell death in MNA cells. While mirin caused accumulation of 53BP1 foci, a marker of DNA damage associated to replication stress, it also inhibited the ATR/CHK1-dependent checkpoint/s, preventing any arrest in the S and G2 phases of the cell cycle. In contrast, mirin induced early occurrence of DNA double strand breaks and a typical DNA damage response (DDR) characterized by ATM, H2AX and p53 phosphorylation culminating in the accumulation of pro-apoptotic p53 target genes. Gain and loss of function experiments confirmed that mirin-induced cell death in MNA cells is p53 dependent. Injection of mirin encapsulated in nanoparticles significantly inhibited tumor growth in a neuroblastoma xenograft model. Overall, these data support the idea that targeting the MRN complex, and perhaps other components of the replication stress response, might be exploited for therapeutic purposes in MNA neuroblastoma.