The mitochondrial voltage-gated potassium channel, Kv1.3, has been emerged as an attractive oncologic target but its function in pancreas cancer (PDAC) is unknown. In this study we evaluated tissue expression of Kv1.3 in resected PDAC from 55 patients and tumor inhibition in orthotopic mouse models using the recently developed Kv1.3 inhibitors PCARBTP and PAPTP. Immunohistochemistry of 55 human PDAC specimens showed that all tumors expressed Kv1.3 with 60% of tumor specimens having high Kv1.3 expression. In pancreas tumor models (Pan02 cells injected into C57BL/6 mice), PCARBTP and PAPTP treatment resulted in tumor reductions of 87% and 70%, respectively. When combined with gemcitabine/abraxane, this increased to 95% and 80% without resultant organ toxicity. In vivo models indicated PCARBTP-mediated cell death occurred through the p38-MAPK pathway. In vitro-generated resistant clones to PCARBTP escaped cell death through upregulation of the anti-oxidant system as determined using SWATH-MS analysis. These data show Kv1.3 is highly expressed in resected human PDAC and the use of novel mitochondrial Kv1.3 inhibitors combined with cytotoxic chemotherapies might be novel, effective treatment for PDAC.