The bromophenol curcumin analog 1,5-bis(3-bromo-4, 5-dimethoxyphenyl) penta-1, 4-dien-3-one (BCA-5) was assayed for antiangiogenic activity. Tandem mass tag labeling and liquid chromatography-tandem mass spectrometry were used to quantify the dynamic changes in the human umbilical vein endothelial cell (HUVEC) proteome. Functional annotation showed that BCA-5 might inhibit compounds related to the extracellular matrix, compounds that possess cytoskeletal protein-binding activity, and compounds that interact with cell motility-related enzymes, indicating antiangiogenic potential. In-vitro experiments have shown that BCA-5 inhibited HUVEC proliferation and induced HUVEC apoptosis. BCA-5 inhibited HUVEC migration, invasion, and tubular formation. BCA-5 decreased the phosphorylation of Akt and endothelial nitric oxide synthase; it also reduced the expression of hypoxia-inducible factor-1α and vascular endothelial cell growth factor in a dose-dependent manner. These results suggest that BCA-5 has antiangiogenic properties and should be considered a potent antiangiogenesis drug for the treatment of cancer.