Background: Robust ERK1/2 activity, which frequently results from KRAS mutation, invariably occurs in pancreatic ductal adenocarcinoma (PDAC). However, direct interference of KRAS signaling has not led to clinically successful drugs. Correct localization of RAF is regulated by the scaffold protein prohibitin (PHB) that ensures the spatial organization between RAS and RAF in plasma membranes, thus leading to activation of downstream effectors. Methods: PHB expression was analyzed in human pancreatic cancer cell lines, normal pancreas, and PDAC tissue. Furthermore, genetic ablation or pharmacological inhibition of PHB was performed to determine its role in growth, migration, and signaling of pancreatic cancer cells in vitro and in vivo. Results: The level of PHB expression was crucial for maintenance of oncogenic ERK-driven pancreatic tumorigenesis. Additionally, rocaglamide (RocA), a small molecular inhibitor, selectively bound to PHB with nanomolar affinity to disrupt the PHB-CRAF interaction by altering its localization to the plasma membrane. Consequently, there was an impairment of oncogenic RAS-ERK signaling, thereby blocking in vitro and in vivo growth and metastasis of pancreatic cancer cells that were addicted to RAS-ERK signaling. More importantly, RocA treatment resulted in a significant increase of the lifespan of tumor-bearing mice without any detectable toxicity. Conclusions: Blockade of the PHB scaffold-CRAF kinase interaction, which is distinct from direct kinase inhibition, may be a new therapeutic strategy to target oncogenic ERK-driven pancreatic cancer.