Chemodynamic therapy (CDT), leveraging intracellular iron ions (Fe) and hydrogen peroxide (HO), is a highly selective therapeutic strategy with significant potential. However, its clinical application is currently hindered by the limited catalytic activity of transition metal ions and insufficient HO supply. In this study, we present a novel and effective CDT approach using an Fe single-atom nanozyme (Fe-SAE) to deliver dihydroartemisinin (DHA), a first-line antimalarial drug. DHA serves dual roles: as a substitute for HO and as a recruiter of Fe, significantly enhancing the reactive oxygen species (ROS) cascade for self-amplified chemodynamic and ferroptosis therapy. Upon internalization by tumor cells, Fe-SAE, with its atomically dispersed active sites, exhibits remarkable peroxidase-like activity, catalyzing the generation of hydroxyl radicals from HO. Simultaneously, the endoperoxide bridge in released DHA is cleaved by Fe-SAE, further generating ROS and inducing lethal lipid peroxidation. DHA also upregulates the expression of transferrin receptor 1 (TfR1), facilitating Fe influx and increasing intracellular Fe levels, thereby enhancing chemodynamic efficacy. Additionally, Fe-SAE@D demonstrates glutathione oxidase-like activity, oxidizing reductive GSH to glutathione disulfide and promoting GPX4 inactivation. Both in vitro and in vivo studies confirm that Fe-SAE@D induces CDT and ferroptosis by self-supplying HO, initiating a ROS storm, and depleting glutathione. These synergistic effects significantly enhance CDT efficacy, presenting a promising strategy to overcome traditional CDT limitations.