Formation of new blood vessels from preexisting vasculature is an indispensable process in tumor initiation, invasion, and metastasis. Novel therapeutic approaches target endothelial cells involved in the process of angiogenesis, due to their genetic stability relative to the rapidly mutating drug-resistant cancer cells. In the present study, we investigated the effect of an active fraction from Emilia sonchifolia, belonging to the family Asteraceae, a plant well known for its anti-inflammatory and antitumor effects, on the inhibition of tumor-specific angiogenesis. Administration of the active fraction from E sonchifolia (AFES; 5 mg/kg, body weight, intraperitoneally) containing the major compound -humulene significantly inhibited B16F10 melanoma-induced capillary formation in C57BL/6 mice. The level of serum vascular endothelial growth factor and serum proinflammatory cytokines such as interleukin-1β, interleukin-6, tumor necrosis factor-α, and granulocyte-macrophage colony-stimulating factor were also reduced significantly. At the same time, administration of AFES significantly enhanced the production of antiangiogenic factors such as tissue inhibitor of matrix metalloproteinase-1. Dose-dependent reduction can be seen in the budding and expansion of microvessels from rat thoracic aorta by AFES treatment. Inhibition of the activation of proenzyme to active enzyme of matrix metalloproteinase along with a successful reduction of proliferation, invasion, and migration of human umbilical vein endothelial cells demonstrated the antiangiogenic effect of AFES in vitro. To date, no study has examined the antiangiogenic activity of this plant with already well-known anti-inflammatory and antitumor effects. Results obtained in the present study by using both in vivo and in vitro angiogenic models altogether proved the inhibitory effect of AFES on tumor-specific neovessel formation.