In this study, we investigated the inhibitory activity of a hot water extract from Sargassum Fulvellum (SFH) against Gluten-induced inflammation and oxidative damages in Caco-2 cell, a human colon epithelial cell. First, we confirmed that SFH improved the cell viability by reducing the intracellular reactive oxygen species (ROS) generation and the formation of apoptotic body in Gluten-stimulated Caco-2 cells without the cytotoxicity. Also, SFH decreased the mRNA expression level of cytokines such as interleukin (IL)-1β, IL-4, IL-8 and tumor necrosis factor (TNF)-α increased by the Gluten stimulation in Caco-2 cells. In addition, SFH effectively modulated the expressions of apoptotic molecules with the reduction of pro-apoptotic molecules, Bax, p53 and cleaved PARP while the increment of the anti-apoptotic molecule, Bcl-2. Moreover, SFH suppressed the nuclear factor (NF)-κB activation by regulating the phosphorylation and degradation of IκB-α as well as the translocation of cytoplasmic NF-κB p65 into the nucleus. Taken together, these results suggest that SFH may be a natural agent with beneficial potentials for the improvment of inflammation and oxidative damages induced by Gluten.