Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to current chemotherapy regimens, in part due to alterations in the p53 tumor suppressor pathway. p53 homolog p63 is a transcription factor essential for the development and differentiation of epithelial surfaces. However its function in cancer is controversial and its role in PDAC is not known. We discovered that ΔNp63α was the predominantly expressed p63 variant in pancreatic cancer cell lines. ΔNp63α protein and mRNA levels were high in T3M4, BxPC3 and COLO-357 pancreatic cancer cells and low in ASPC-1 and PANC-1 cells. Overexpression of ΔNp63α in PANC-1 cells and shRNA-mediated knockdown in T3M4 cells indicated that ΔNp63α promoted anchorage-dependent and -independent growth, motility and invasion, and enhanced resistance to cisplatin-induced apoptosis. Epidermal growth factor receptor (EGFR) signaling pathways contribute to the biological aggressiveness of PDAC, and we found that the motogenic effects of ΔNp63α were augmented in presence of EGF. Ectopic expression of ΔNp63α resulted in upregulation of EGFR and β1-integrin in PANC-1 cells. Conversely, ΔNp63α knockdown had an opposite effect in T3M4 cells. ΔNp63α potentiated EGF-mediated activation of ERK, Akt and JNK signaling. Chromatin immunoprecipitation and functional reporter assays demonstrated that ΔNp63α activated EGFR transcription. 14-3-3σ transcription was also positively regulated by ΔNp63α and we have previously shown that 14-3-3σ contributes to chemoresistance in pancreatic cancer cell lines. Conversely, shRNA-mediated knockdown of 14-3-3σ led to abrogation of the ΔNp63α effects on cell proliferation and invasion. Thus, p53 homolog ΔNp63α enhances the oncogenic potential of pancreatic cancer cells through trans-activation of EGFR and 14-3-3σ.