Acute kidney injury (AKI), characterized by a rapid decline in renal function, is associated with impaired mitochondrial function and excessive reactive oxygen species (ROS). Therefore, the exploration of ROS scavengers provides promising new opportunities for the prevention and treatment of AKI by mitigating oxidative stress. Here, we construct an ultrasmall platinum single-atom enzyme (Pt/SAE) with multiple antioxidant enzyme activities to protect against acute kidney ischemia-reperfusion (I/R) injury. Pt/SAE not only mimics superoxide dismutase and catalase activities to convert superoxide anion into water and oxygen, but also exhibits impressive hydroxyl radical scavenging capacity, thereby reducing pro-inflammatory macrophage levels and preventing inflammation. Furthermore, Pt/SAE reduces the accumulation of Z-form DNA, which excessively accumulates following I/R damage, thus decreasing its interaction with Z-DNA binding protein 1, consequently preventing the progression of PANoptosis following I/R stress. Additionally, the downregulation of ROS levels induced by Pt/SAE suppresses lipid peroxidation, which in return preventing the progression of ferroptosis following I/R. Both in vitro and in vivo experiments confirm that Pt/SAE effectively mitigates inflammatory cell infiltration and promotes a shift in macrophage polarization from the M1-like to M2-like subtype. This study provides promising information for the development of novel SAEs as a viable treatment method for AKI.