Pancreatic cancer remains a recalcitrant neoplasm associated with chemoresistance and high fatality. Because it is frequently resistant to apoptosis, exploiting autophagic cell death could oﬀer a new treatment approach. We repurpose echinomycin, an antibiotic encapsulated within a syndecan-1 actively targeted nanoparticle, for treatment of pancreatic cancer. Tumor-speciﬁc uptake, biodistribution, eﬃcacy of nanodelivered echinomycin, and mechanism of cell death were assessed in aggressive, metastatic models of pancreatic cancer. In these autophagic-dependent pancreatic cancer models, echinomycin treatment resulted in autophagic cell death noted by high levels of LC3 among other autophagy markers, but without hallmarks of apoptosis, e.g., caspase activation and chromatin fragmentation, or necrosis, e.g., plasma membrane degradation and chromatin condensation/degrading. In vivo, biodistribution of syndecan-1-targeted nanoparticles indicated preferential S2VP10 or S2CP9 tumor uptake compared to the liver and kidney (S2VP10 p = 0.0016, p = 0.00004 and S2CP9 p = 0.0009, p = 0.0001). Actively targeted nanodelivered echinomycin resulted in signiﬁcant survival increases compared to Gemzar (S2VP10 p = 0.0003, S2CP9 p = 0.0017) or echinomycin only (S2VP10 p = 0.0096, S2CP9 p = 0.0073). We demonstrate that actively targeted nanodelivery of echinomycin results in autophagic cell death in pancreatic and potentially other high-autophagy, apoptosis-resistant tumors. Collectively, these ﬁndings support syndecan-1-targeted delivery of echinomycin and dysregulation of autophagy to induce cell death in pancreatic cancer.