Angiogenesis, the formation of new blood vessels, is tightly regulated in the normal organism. Excessive angiogenesis can have detrimental consequences in various processes, including promoting uncontrolled tumor growth. Inhibiting angiogenesis using natural compounds is an important focus in developing new cancer treatment strategies. Ginsenoside Rh2 (G-Rh2), a natural product derived from red ginseng, has been reported to have therapeutic effects on some tumors, but its antiangiogenic effects in zebrafish has not been evaluated. Here we investigated the antiangiogenic of G-Rh2 using the zebrafish angiogenesis model. Morphological observations of the G-Rh2-treated wild-type embryos were performed to evaluate the toxicity of the compound. Tg(fli1-EGFP) transgenic zebrafish with fluorescent blood vessels were studied to evaluate vascular development defects. G-Rh2 treatment up to 84.85 μM did not induce morphological defects in zebrafish. We observed suppression effect of angiogenesis by G-Rh2 in inhibiting intersegmental vessel formation from 30 to 84.85 μM in a dose-dependent manner. Moreover, quantitative real-time PCR revealed that G-Rh2 suppressed vascular endothelial growth factor (vegf) mRNA expression but not mRNA expression of its receptors (flt1, kdr). Western blot further confirmed that G-Rh2 treatment resulted in reduced Vegf protein expression. Our study suggested that G-Rh2 may exert anti-angiogenic activity by downregulation of Vegf in zebrafish embryos, thus indicating its role as a potential therapeutic agent against cancer.