Microalgae are primary producers in marine ecosystems, and have been diffusely used in medicine and food. In this research, we evaluated the protective effects of polypeptides from microalgae, Isochrysis zhanjiangensis (EMFGTSSET, ETT) on endothelial injury in angiotensin II (Ang II)-induced human umbilical vein endothelial cells (HUVEC). The results showed that ETT inhibited the fluorescence intensity of intracellular reactive oxygen species (ROS), and reduces the expression of related cytokines, such as IL-1(i, IL-8, TNF-alpha, iNOS, COX-2, ET-1, AT-1, and adhesion factor. It blocks inflammation and apoptosis through mitogen-activated protein kinases (MAPK), nuclear factor kappa B (NF-kappa B) and serine/threonine kinase (Akt) signal pathways, thereby alleviating endothelial damage. Meanwhile, ETT (IC50 = 15.08 mu M) antagonizes Angiotensin-I Converting Enzyme (ACE) in a non-competitive binding mode, and has an antihypertensive effect in spontaneously hypertensive rats (SHR). Therefore, ETT has excellent effect in regulating hypertension, can become the main component of potential functional food for the prevention of cardiovascular diseases, and further improve the use value of Isochrysis Zhanjiangensis.