The current management of primary osteosarcoma (OS) and its secondary metastasis is limited by the lack of an efficient drug delivery system. Here we report of an in situ gelling chitosan/dipotassium orthophosphate hydrogel system designed to directly deliver the frontline chemotherapeutic agent (doxorubicin) in a sustained time period to tumor sites. A significant reduction of both primary and secondary OS in a clinically relevant orthotopic model was measured when doxorubicin was administered with the hydrogel. This hydrogel delivery system also reduced cardiac and dermal toxicity of duxorubicin in mice. The results obtained from this study demonstrate the potential application of a biodegradable hydrogel technology as an anti-cancer drug delivery system from successful chemotherapy.