Single-atom nanozymes (SAzymes) are considered promising alternatives to natural enzymes. The catalytic performance of SAzymes featuring homogeneous, well-defined active structures can be enhanced through elucidating structure-activity relationship and tailoring physicochemical properties. However, manipulating enzymatic properties through structural variation is an underdeveloped approach. Herein, we report on the synthesis of edge-rich Fe single-atom nanozymes (FeNC-edge) via an H2O2-mediated edge generation. By controlling the number of edge sites, the peroxidase (POD)- and oxidase (OXD)-like performance is significantly enhanced. The activity enhancement results from the presence of abundant edges, which provide new anchoring sites to mononuclear Fe. Experimental results combined with density functional theory (DFT) calculations reveal that FeN4 moieties in the edge sites display high electron density of Fe atoms and open N atoms. Finally, we demonstrate that FeNC-edge nanozyme effectively inhibits tumor growth both in vitro and in vivo, suggesting that edge-tailoring is an efficient strategy for developing artificial enzymes as novel catalytic therapeutics.