Despite aggressive treatments, pancreatic ductal adenocarcinoma (PDAC) remains an intractable disease, largely because it is refractory to therapeutic interventions. To overcome its nutrient-poor microenvironment, PDAC heavily relies on autophagy for metabolic needs to promote tumor growth and survival. Here, we explore autophagy inhibition as a method to enhance the effects of radiotherapy on PDAC tumors. Hydroxychloroquine is an autophagy inhibitor at the focus of many PDAC clinical trials, including in combination with radiotherapy. However, its acid-labile properties likely reduce its intratumoral efficacy. Here, we demonstrate that EAD1, a synthesized analogue of HCQ, is a more effective therapeutic for sensitizing PDAC tumors of various KRAS mutations to radiotherapy. Specifically, in vitro models show that EAD1 is an effective inhibitor of autophagic flux in PDAC cells, accompanied by a potent inhibition of proliferation. When combined with radiotherapy, EAD1 is consistently superior to HCQ not only as a single agent, but also in radiosensitizing PDAC cells, and perhaps most importantly, in decreasing the self-renewal capacity of PDAC cancer stem cells (PCSC). The more pronounced sensitizing effects of autophagy inhibitors on pancreatic stem over differentiated cells points to a new understanding that PCSCs may be more dependent on autophagy to counter the effects of radiation toxicity, a potential mechanism explaining the resistance of PCSCs to radiotherapy. Finally, in vivo subcutaneous tumor models demonstrate that combination of radiotherapy and EAD1 is the most successful at controlling tumor growth. The models also confirmed a similar toxicity profile between EAD1 and Hydroxychloroquine.