Uveal melanoma (UM), the most common primary intraocular malignancy in adults, faces significant therapeutic challenges due to chemoresistance and high metastatic potential. Although melphalan (Mel), a DNA-alkylating agent, is used for local tumor control, its efficacy is limited by drug resistance and retinal toxicity. Here, we report an injectable nanocatalytic hydrogel system (PS@LDO/Mel) designed to enhance chemosensitization by synergizing reactive oxygen species (ROS) generation and glutathione (GSH) depletion. The system integrates manganese-doped layered double oxide (MgFeMn-LDO) with Mel within a thiol-maleimide hydrogel, enabling controlled drug release and intraocular localization. Mn/Fe multimetallic synergy in MgFeMn-LDO enhanced GSH depletion by 15.15-fold compared to undoped MgFe-LDO within 60 min. In vitro studies demonstrated that PS@LDO/Mel elevated ROS levels and reduced GSH content, increasing apoptosis rates in OMM2.3 cells from 33.3% (Mel alone) to 70.1% while suppressing cell invasion. In murine models, the system effectively inhibited primary tumor growth through amplified DNA damage and mitochondrial apoptosis. By addressing limitations of conventional therapies, such as poor tumor targeting and uncontrolled drug release, this work provides a localized, multifunctional strategy for early-stage UM intervention, highlighting the potential of nanocatalytic hydrogels in ophthalmic oncology.