Phlorotannin is a bioactive secondary metabolite from the brown algae. In this paper, phlorotannin and antioxidant activities from the ethanol extracts of Sargassum seratum collected in January 2011 in Nha Trang bay, Viet Nam were studied to optimize extraction process through BoxBehnken design. The experiment was optimized by Nemrodw software. Antioxidant activities, such as, total antioxidant, reducing power, DPPH free radical scavenging were studied. Research factors include extraction temperature range, X1 (24-60oC), extraction time, X2 (12-16 hours) and solvent-to-material ratio, X3 (15-5- v/w). The results showed that optimization values such as phlorotannin content (Y1), total antioxidant activity (Y2) and reducing power activity (Y3) corresponded to 6.13 mg, 15.9 mg acid ascorbic and 46.6 mg FeSO4/ 1g dry material (DM), respectively and the optimal conditions were 43°C, 33 hour and 27:1 (v/w). Some chemical components in the optimal extract also were qualiatively evaluated such as fats, flavonoid, alkaloid, terpenoid and oil.