DCC functions as a tumor suppressor and is altered in various tumors, including neuroendocrine neoplasms. Netrin (NTN)-1 serves as the primary ligand for DCC. Operating as a dependence receptor, DCC induces apoptosis without NTN and promotes cell survival in its presence. In specific cancers like small-cell lung cancer and neuroblastoma, upregulation of NTN-3 rather than NTN-1 has been observed. However, the precise involvement of NTNs and DCC in PNEN remains unclear. We assessed DCC and netrin expression in pancreatic neuroendocrine neoplasms (PNEN) cells (BON-1). We examined netrin's effect on cell viability using DCC knockdown and NP137, a netrin-inhibiting antibody. In vivo, PNEN cells were injected into nude mice and treated with NP137 or PBS. Tumor RNA sequencing was performed. A population-based analysis using TCGA data evaluated DCC and NTN3 expression on survival. BON-1 cells exhibited elevated expression of DCC and NTN-3. The addition of NTN-1 augmented BON1 viability, a response lessened upon NTN blockade using NP137. Furthermore, DCC siRNA negated the effect of NTN-1 on cell viability. Mice bearing PNEN BON-1 xenografts and treated with NP137 exhibited markedly diminished xenograft growth. RNA sequencing revealed upregulation of small nucleolar RNAs (SNORs) in NP137-treated tumors, with enriched pathways related to RNA processing. TCGA analysis showed a negative correlation between NTN3 expression and survival. Our data suggest that NTN-3, NTN-1, and DCC play co-dependent oncogenic roles in PNENs that are reversible by inhibiting NTN binding to DCC. NTN inhibition merits further investigation as a potential therapeutic target.