<p>Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer deaths in North America with ~12% survival 5 years after diagnosis. Risk factors for PDAC, including smoking and chronic pancreatitis, trigger the unfolded protein response (UPR). Global deletion of Activating Transcription Factor 3 (ATF3), a UPR mediator, restricts preneoplastic progression in mice expressing oncogenic KRAS (KRAS^G12D). However, ATF3 is expressed in malignant and non-malignant cells suggesting it may affect multiple cell compartments in PDAC. Therefore, the goal of this study was to determine if ATF3 has epithelial-specific roles during PDAC initiation. Epithelial cells from mice expressing KRAS^G12D with (<i>Ptf1a</i>^{<i>creERT/+</i>}<i>KRAS</i>^{<i>G12D</i>/+}) or without ATF3 (<i>Atf3</i>^{<i>−/−</i>}<i>Ptf1a</i>^{<i>creERT/+</i>}<i>KRAS</i>^{<i>G12D/+</i>}<i>; APK</i>) were characterized before and after pancreatic injury. Additionally, mice allowing acinar-specific <i>Atf3</i> deletion and KRAS^G12D expression (<i>A</i>^{<i>acinar</i>}<i>PK</i>) were compared to <i>Ptf1a</i>^{<i>creERT/+</i>}<i>KRAS</i>^{<i>G12D</i>/+} and <i>APK</i> mice following injury. RNA-seq revealed reduced oncogenic pathways in <i>APK</i> acinar cells consistent with reduced ADM formation in <i>APK</i> cultures. <i>Ptf1a</i>^{<i>creERT/+</i>}<i>KRAS</i>^{<i>G12D</i>/+} and <i>APK</i> organoids showed differential gene expression and morphology, with <i>APK</i> organoids exhibiting reduced viability. In vivo, <i>APK</i> and <i>A</i>^{<i>acinar</i>}<i>PK</i> tissue showed restricted neoplastic progression and KRAS signaling compared to <i>Ptf1a</i>^{<i>creERT/+</i>}<i>KRAS</i>^{<i>G12D</i>/+} mice. This study indicates ATF3 works in a cell autonomous fashion, and its absence restricts <i>KRAS</i>^<i>G12D</i>-mediated PDAC.</p>