Phosphatidylinostiol-trisphosphate (PIP₃) is involved in the formation of lamellipodium during cell migration. PI3K is activated by multiple signaling pathways through GPCRs and RTKs, and it is responsible for phosphorylation of PIP₂ to PIP₃ which is the activation site for AKT and PDK. VPAC2, also known as VIPR2, is a secretin family GPCR that binds two homologous neuropeptides with high affinity, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). We previously found that VIP increased migration of cancer cells, but the underlying mechanism remains unclear. Here we investigated the involvement of the PI3K pathway in VIP-induced cell migration. In HeLa cells overexpressing VPAC2, VPAC2 was abundantly localized to lamellipodia in the presence of VIP, and PIP₃ levels on the plasma membrane were increased. Conversely, VPAC2-silencing reduced VIP-induced increase in PIP₃ levels on the plasma membrane. Silencing of VPAC2 in MCF-7 cells inhibited VIP-induced cell migration. In contrast, MCF-7 cells stably expressing VPAC2 exhibited the increased lamellipodium extension and cell migration in vitro and in vivo. These findings suggest that VIP promotes cancer cell migration by enhancing PIP₃ synthesis through activation of VPAC2 receptors.