Sunitinib (SUN) is a multi-targeted receptor tyrosine kinase inhibitor (TKI) that may lead to drug resistance and metastasis because of increased cancer stem-like cells (CSCs) due to the induction of hypoxia. Our group has proved that dopamine (DA) can specifically reduce CSC frequency and enhance the response of SUN in drug-resistant breast cancerand non-small cell lung cancer (NSCLC). In this study, DA and SUN combination therapy was investigated in the treatment of pancreatic cancer, a malignant tumor with high mortality rate and very limited therapies. The cytotoxicity assay, clone formation assay and wound healing assay in two pancreatic cancer cell line PANC-1 and SW1990 showed that DA could significantly increase the effect of SUN on cell survival, clone formation ability and migration ability. Besides, SW1990 cell-derived xenograft model and a pancreatic cancer patient-derived xenograft (PDX) model were constructed, further proving that DA could increase the in vivo anti-tumor efficacy of SUN, and could be reversed by SCH23390, a D1 dopamine receptor (D1DR) antagonist. Moreover, the CSC frequency of the combination groups was lower than the control groups or SUN monotherapy groups. In addition, the body weight, H&E staining and blood routine test results showed that the combination therapy was safe. In summary, DA and SUN combination therapy could be a promising strategy for the treatment of pancreatic cancer.