Pancreatic cancer is regarded as the most lethal solid tumor worldwide. Deregulated and constitutively activated NF-κB signaling is one of the major characteristics of pancreatic cancer. The total expression level and subcellular localization of RelA/p65 have been shown to determine the activation of canonical NF-κB signaling in pancreatic cancer. FGD3, which is involved in regulating the actin cytoskeleton and cell shape, has been reported to inhibit cancer cell migration and predict a favorable prognosis in multiple types of cancer. However, the specific role of FGD3 in pancreatic cancer is still unknown. In this study, we conducted a systematic investigation of the cancer-related role of FGD3 in pancreatic cancer. We demonstrated that FGD3 was abnormally downregulated in pancreatic cancer tissues and that low expression of FGD3 was associated with unfavorable prognosis in patients with pancreatic cancer. Then, we showed that FGD3 inhibited pancreatic cancer cell proliferation, invasion and metastasis in vivo and in vitro. Moreover, we revealed that FGD3 silencing activated the NF-κB signaling pathway by promoting HSF4 nuclear translocation and increasing p65 expression in pancreatic cancer cells. Therefore, our results identified a novel and targetable FGD3/HSF4/p65 signaling axis in pancreatic cancer cells.