Our previous study evaluated the in vitro and in vivo antioxidant activities of sulfated polysaccharides from a Celluclastassisted extract of Hizikia fusiforme (HFPS). The results indicate that HFPS possesses potent antioxidant activity and suggest the potential use of HFPS to combat photoaging. In this study, we investigated the ultraviolet (UV) protective effect of HFPS in vitro in keratinocytes (HaCaT cells) and in vivo in zebrafish. The results indicate that HFPS significantly reduced the level of intracellular reactive oxygen species (ROS) and improved the viability of UVB-irradiated HaCaT cells. In addition, HFPS remarkably decreased apoptosis formation in UVB-irradiated HaCaT cells in a dose-dependent manner. The in vivo test results also demonstrate that HFPS significantly reduced intracellular ROS levels, cell death, NO production, and lipid peroxidation levels in UVB-irradiated zebrafish in a dose-dependent manner. These results suggest that HFPS possesses strong in vitro and in vivo UV-protective effects, making it a potential ingredient in the cosmeceutical industry.