Sargassum fusiforme (Harv.) is a brown alga belonging to the Sargasaceae family. The Sargassum fusiforme polysaccharides (SFPS) have demonstrated good anti-tumor and immunomodulatory activity. However, the underlying mechanisms of its anti-tumorigenesis, especially the anti-angiogenic activity is yet to be established. In the present study, we attempted to determine the effects of SFPS on the human lung adenocarcinoma SPC-A-1 cells and its xenograft model. The results showed that SFPS provides a concentration-dependent inhibition of SPC-A-1 cell proliferation in in vitro and the tumor growth in in vivo studies. Immunohistochemistry studies revealed that the administration of SFPS significantly decreased CD31, VEGF-A expression and the tumor microvessel density (MVD). SFPS also provided a dose-dependent impairment of cell vitality, induction of cell cycle arrest and apoptosis of human umbilical vein endothelial cells (HUVECs). SFPS inhibited the expression of VEGF-A in tumor cells and its receptor VEGFR2 in HUVECs. The HUVEC tube formation assay showed that SFPS could abrogate the tube formation with relatively decreased tubes length of tube-like capillary similar to anti-VEGF antibody, Avastin®. These findings suggested that SFPS could be used as an alternative anticancer drug as they inhibited the angiogenesis and the microvessel formation through disruption of VEGF signals apart from direct tumor cytotoxicity.