One of the most promising strategies for the controlled release of therapeutic molecules is stimuli-responsive and biodegradable hydrogels developed from natural polymers. However, current strategies to development stimuli-responsive hydrogels lack precise control over drug release profile and use cytotoxic materials during preparation. To address these issues, multi-stimuli responsive hydrogels derived from hyaluronic acid and diselenide based cross-linker were developed for the controlled release of doxorubicin (DOX). Hydrogels were rapidly formed via an inverse electron demand Diels-Alder click chemistry and encapsulated DOX/indocyanine green (ICG) in their porous networks. The hydrogels showed a rapid release of DOX in acidic (pH 5), reducing (10 mmol DTT), and oxidizing medium (0.5% HO), and after NIR irradiation. The in vitro experiments demonstrated that hydrogels were highly cytocompatible and the DOX-loaded hydrogels induced similar anti-tumor effect as compared to that of the free-DOX. Furthermore, DOX + ICG loaded hydrogels increased the antitumor efficacy of DOX after NIR irradiation.