Purpose: Resistance to chemotherapeutics is an eminent cause which leads for search of options that help in diminution of Pancreatic Ductal Adenocarcinoma (PDAC) by overcoming resistance issues. Caffeic acid (CFA), a polyphenol occurring in many dietary foods is known to show anti-diabetic and anticancer properties potential.Methods: To unveil effect of CFA on PDAC we carried out this research in PDAC cells, following which we checked combination effect of CFA and chemotherapeutics and pre-sensitization effects of CFA. Multitudinous web-based approaches were applied for identifying CFA targets in PDAC and then getting their interconnections.Results and conclusions: Subsequently, we manifested CFA affects by in-vitro analysis showing IC50 concentrations of 37.37µM and 15.06µM on Panc-1 and Mia-PaCa-2 respectively. Combination index of CFA with different drugs was explored that gave no significant results leading to further investigate pre-sensitizing effects. CFA pre-sensitization reduced IC50 concentration of doxorubicin in both PDAC cell lines which also triggered ROS generation determined by DCFH-DA assay. Gene expression analysis revealed that CFA acts differently on both cell lines and triggers distinct signalling to overcome resistance. Collectively, this study investigated role of CFA as PDAC therapeutics and explored mechanism in mitigating resistance of PDAC by sensitizing to chemotherapeutics.