HSP70-mediated mitochondrial dynamics and autophagy represent a novel vulnerability in pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is highly aggressive and has limited treatment options. Overexpression of HSP70 is a hallmark of cancer, associated with poor prognosis. This study shows that PDAC has the highest HSP70 expression compared to normal tissue. HSP70 inhibition alters mitochondrial subcellular localization, impairs mitochondrial dynamics, and promotes mitochondrial swelling, leading to apoptosis. Mechanistically, HSP70 inhibition suppresses PINK1-mediated phosphorylation of DRP1, a key regulator of mitochondrial dynamics. Treatment with the HSP70 inhibitor AP-4-139B is effective in PDAC models. Additionally, HSP70 inhibition promotes AMPK-mediated phosphorylation of Beclin-1, a key regulator of autophagy. The autophagy inhibitor hydroxychloroquine enhances the anti-tumor effects of AP-4-139B. These findings suggest that HSP70 is a multi-functional driver of tumorigenesis that regulates mitochondrial dynamics and autophagy. Concurrent inhibition of HSP70 and autophagy may represent a novel therapeutic strategy for HSP70-driven PDAC. The study demonstrates that HSP70 inhibition impairs mitochondrial function, induces ROS production, and disrupts mitochondrial dynamics. HSP70 inhibition also limits cancer cell migration and metastasis in vitro and in vivo. AP-4-139B shows single-agent efficacy in PDAC cells and xenograft models. HSP70 inhibition induces autophagic flux in PDAC cells, which is enhanced by autophagy inhibitors. The combination of HSP70 and autophagy inhibition synergistically suppresses PDAC progression. These findings highlight the potential of targeting HSP70 and autophagy as a novel therapeutic approach for PDAC.HSP70-mediated mitochondrial dynamics and autophagy represent a novel vulnerability in pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is highly aggressive and has limited treatment options. Overexpression of HSP70 is a hallmark of cancer, associated with poor prognosis. This study shows that PDAC has the highest HSP70 expression compared to normal tissue. HSP70 inhibition alters mitochondrial subcellular localization, impairs mitochondrial dynamics, and promotes mitochondrial swelling, leading to apoptosis. Mechanistically, HSP70 inhibition suppresses PINK1-mediated phosphorylation of DRP1, a key regulator of mitochondrial dynamics. Treatment with the HSP70 inhibitor AP-4-139B is effective in PDAC models. Additionally, HSP70 inhibition promotes AMPK-mediated phosphorylation of Beclin-1, a key regulator of autophagy. The autophagy inhibitor hydroxychloroquine enhances the anti-tumor effects of AP-4-139B. These findings suggest that HSP70 is a multi-functional driver of tumorigenesis that regulates mitochondrial dynamics and autophagy. Concurrent inhibition of HSP70 and autophagy may represent a novel therapeutic strategy for HSP70-driven PDAC. The study demonstrates that HSP70 inhibition impairs mitochondrial function, induces ROS production, and disrupts mitochondrial dynamics. HSP70 inhibition also limits cancer cell migration and metastasis in vitro and in vivo. AP-4-139B shows single-agent efficacy in PDAC cells and xenograft models. HSP70 inhibition induces autophagic flux in PDAC cells, which is enhanced by autophagy inhibitors. The combination of HSP70 and autophagy inhibition synergistically suppresses PDAC progression. These findings highlight the potential of targeting HSP70 and autophagy as a novel therapeutic approach for PDAC.