Background Angiogenesis is vital in the process of primary tumor growth and metastasis. Ca2+ signaling is crucial for tumor angiogenesis. This study aimed to detect the potential role of Ca2+ permeable transient receptor potential vanilloid-3 (TRPV3) in the angiogenesis of non-small cell lung cancer (NSCLC). Methods Small interfering RNA was used to down-regulate TRPV3 expression in A549 cells. A laser scanning confocal microscope was used to examine intracellular calcium concentration ([Ca2+]i). HUVECs tube formation and migration assay, Western blot, MTT and ELISA were performed to detect the potential mechanisms of TRPV3 in tumor angiogenesis. A mouse tumor xenograft model was performed to expound the effects of TRPV3 on tumor cell growth. Results Inhibition of TRPV3 reduced [Ca2+]i and protein expression of VEGF and HIF-1α in A549 cells. Moreover, HIF-1α depletion decreased the VEGF secretion level and expression. Depletion of TRPV3 inhibits HUVECs proliferation, tube formation and migration induced by conditioned medium. And TRPV3 inhibition could decrease the volume of xenograft tumors, MVD of CD34+ cells. HIF-1α, VEGF and p-CaMKП expression levels in the xenograft tumors of RuR and siTRPV3 groups was reduced. Conclusions TRPV3 calcium channel protein may play a key role in NSCLC angiogenesis. TRPV3 could promote the angiogenesis through HIF-1α-VEGF signaling pathway. Targeting TRPV3 channel protein by novel approaches would be useful for reversing NSCLC angiogenesis.