Chemodynamic therapy (CDT) based on multifunctional nanoparticles (NPs) has occurred as an attractive cancer treatment that covers the shortage of nonnegligible limitations from single therapy. Herein, we synthesize a safe and universal CDT nanoparticle—iron single-atom nanoparticle (Fe SANP), in which Fe single-atom as the active catalytic site is anchored in a carbon framework with encapsulated doxorubicin (DOX). Fe SANPs work as catalase-like nanozyme for hydroxyl radicals (●OH) production. The prepared NPs (denoted as DOX@Fe SANPs) can efficiently mediate peroxidase-like activity with the existence of H2O2 that enhances cancer cell elimination by generating abundant ●OH. DOX@Fe SANPs exhibit a pHinduced degradable character that contributes to specific drug release in the tumor microenvironment (TME). DOX@Fe SANPs produce ignorable systematic toxicity after biodegradation and drug delivery processes. Collectively, this study highlights the efficient anti-tumor performances of the iron single-atom nanocatalysts containing an anti-cancer drug DOX.