The clinical application of combination chemotherapy with cisplatin is unsatisfactory for most pancreatic cancer patients with wild-type BRCA1/2 or PALB2 due to resistance. Genes associated with cisplatin resistance in patients without BRCA1/2 or PALB2 mutations should be pursued. Through bioinformatics analysis, we found that Myotrophin (MTPN) expression was correlated with that of nuclear factor kappa B (NF-κB), a protein involved in the regulation of cisplatin sensitivity. Immunohistochemistry revealed that MTPN was more highly expressed in human pancreatic cancer tissues than in normal tissues. MTPN promoted the malignant biological behaviors of pancreatic cancer (PC) cells and activated the epithelial-mesenchymal transition process. Furthermore, MTPN was found to induce cisplatin resistance in PC cells and upregulate BRCA1/2 while promoting DNA repair. The enhancing effects of MTPN on cisplatin resistance and BRCA1/2 up-regulation were abolished by an inhibitor of IκBα phosphorylation. These studies suggested that MTPN may increase cisplatin resistance by activating IκBα to regulate BRCA1/2 expression. In summary, targeting MTPN could be a potential therapeutic strategy, as MTPN knockdown increased the sensitivity to cisplatin-based chemotherapy in pancreatic cancer with wild-type BRCA1/2.