Oxymatrine, the main alkaloid component in the traditional Chinese herbal medicine Sophora japonica (Sophora flavescens Ait), has been reported to have antitumor properties. However, the mechanisms of action in human pancreatic cancer are not well established to date. In the present study, we investigated the antiangiogenic effects of oxymatrine on human pancreatic cancer as well as the possible mechanisms involved. The results of the cell viability assay showed that treatment of PANC-1 pancreatic cancer cells with oxymatrine resulted in cell growth inhibition in a dose- and time-dependent manner. To investigate the possible mechanisms involved in these events, we performed western blotting and reverse transcription-polymerase chain reaction (RT-PCR) analysis. The results revealed that oxymatrine decreased the expression of angiogenesis-associated factors, including nuclear factor κB (NF-κB) and vascular endothelial growth factor (VEGF). Finally, the antiproliferative and antiangiogenic effects of oxymatrine on human pancreatic cancer were further confirmed in pancreatic cancer xenograft tumors in nude mice. In conclusion, our studies for the first time suggest that oxymatrine has potential antitumor effects on pancreatic cancer via suppression of angiogenesis, probably through regulation of the expression of the NF-κB-mediated VEGF signaling pathway.