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Our previous study reported that the marine dietary bioactive compound fucoxanthin (FX) has the potential to reduce the level of oxidation in retinal Müller cells (RMCs) induced by ultraviolet B (UVB) irradiation. However, the gastrointestinal environment can inhibit the bioavailability and absorption of FX in the cell systems. In the current study, FX was initially digested in a simulated in vitrogastrointestinal fluid. Nine main digestive products were identified, and the photoprotective activities of FX simulated in vitrogastrointestinal digestion products (FX-ID) were assessed in the same RMC model. FX-ID significantly reduced intracellular ROS and alleviated apoptosis. Western blot assays showed that FX-ID inhibited phosphorylated proteins in the MAPK and NF-κB signaling pathways. Our proteomics analysis revealed that the differentially expressed proteins were linked to biological networks associated with antioxidation and metabolic processes. The data may provide insight into the photoprotective mechanisms of FX-ID and promote the development of various functional foods to prevent retinal disorders.