The rhizome of Alpinia officinarum Hance, a popular spice used as a condiment in China and Europe, has various reported bioactivities, including anticancer, anti-inflammatory and antioxidant effects. However, its anti-angiogenic activity has not previously been reported. In this study, a diarylheptanoid was isolated from Alpinia officinarum and identified as 1-phenyl-7-(4-hydroxy-3-methoxyphenyl)-4E-en-3-heptanone (PHMH). We demonstrated that PHMH exerts anti-angiogenic activity both in vitro and in vivo. PHMH inhibited vascular endothelial growth factor (VEGF)-induced viability, migration, invasion and tube formation in human umbilical vein endothelial cells (HUVECs) in vitro, and also suppressed VEGF-induced sprout formation of rat aorta ex vivo. Furthermore, PHMH was found to block VEGF-induced vessel formation in mice and suppress angiogenesis in both zebrafish and chorioallantoic membrane models. Mechanistic studies indicated that PHMH inhibited VEGF-induced VEGF receptor-2 (VEGFR-2) auto-phosphorylation and resulted in the blockage of VEGFR-2-mediated signaling cascades in HUVECs, including the Akt/mTOR, ERK1/2, and FAK pathways. Our findings provide new insights into the potential application of PHMH as a therapeutic agent for anti-angiogenesis.