Studies have shown thatSargassum fusiformeand its extracts are effective herbal treatments for leukemia. We previously found that a polysaccharide fromSargassum fusiforme, SFP 2205, stimulated apoptosis in human erythroleukemia (HEL) cells. However, the structural characterization and antitumoral mechanisms of SFP 2205 remain uncertain. Here, we studied the structural characteristics and anticancer mechanisms of SFP 2205 in HEL cells and a xenograft mouse model. The results demonstrated that SFP 2205, with a molecular weight of 41.85 kDa, consists of mannose, rhamnose, galactose, xylose, glucose, and fucose with monosaccharides composition of 14.2%, 9.4%, 11.8%, 13.7%, 11.0%, and 38.3%, respectively. On animal assays, SFP 2205 significantly inhibited growth of HEL tumor xenografts with no discernible toxicity to normal tissues. Western blotting showed that SFP 2205 therapy improved Bad, Caspase-9, and Caspase-3 protein expression, and ultimately induced HEL tumor apoptosis, indicating mitochondrial pathway involvement. Furthermore, SFP 2205 blocked the PI3K/AKT signaling pathway and 740 Y-P, an activator of the PI3K/AKT pathway, rescued the effects of SFP 2205 on HEL cell proliferation and apoptosis. Overall, SFP 2205 may be a potential functional food additive or adjuvant for preventing or treating leukemia.