Lipid peroxidation means the oxidative degradation of lipids. The process from the cell membrane lipids in an organism is generated by free radicals, and result in cell damage. Phlorotannins, well-known marine brown algal polyphenols, have been utilized in functional food supplements as well as in medicine supplements to serve a variety of purposes. In this study, we assessed the potential anti-lipid peroxidation activity of phlorofucofuroeckol-A (PFF-A), one of the phlorotannins, isolated from Ecklonia cava by centrifugal partition chromatography in 2,2-azobis (2-amidinopropane) dihydrochloride (AAPH)-stimulated Vero cells and zebrafish system. PFF-A showed the strongest scavenging activity against alkyl radicals of all other reactive oxygen species (ROS) and exhibited a strong protective effect against ROS and a significantly strong inhibited of malondialdehyde in AAPH-stimulated Vero cells. The apoptotic bodies and pro-apoptotic proteins Bax and caspase-3, which were induced by AAPH, were strongly inhibited by PFF-A in a dose-dependent manner and expression of Bcl-xL, an anti-apoptotic protein, was induced. In the AAPH-stimulated zebrafish model, additionally PFF-A significantly inhibited ROS and cell death, as well as exhibited a strong protective effect against lipid peroxidation. Therefore, these results suggest that PFF-A has excellent protective effects against ROS and lipid peroxidation induced by AAPH in both an in vitro Vero cell model and an in vivo zebrafish model.