Acute kidney injury (AKI) is a heterogeneous disorder frequently occurring in hospitalized patients with multiple comorbidities. Chemotherapy-associated AKI (e.g., cisplatin-induced AKI, CP-AKI) and rhabdomyolysis-induced AKI (RM-AKI) are initiated by the excessive accumulation of reactive oxygen species (ROS). Herein, metal phenolic networks (MPNs) composed of copper (II) (Cu), a typical cofactor in the native superoxide dismutase (SOD), and a well-studied natural antioxidant curcumin (Cur) (denoted as Cur-Cu) were fabricated to integrate the ROS-scavenging properties of metal ions and polyphenols. The results indicate that Cur-Cu nanoparticles (NPs) possessed robust antioxidative enzyme-like activities. Meanwhile, Cur-Cu NPs with polyethylene glycol (PEG) covalent modification (Cur-Cu@PEG) abolished the ROS-triggered oxidative damage of HK-2 cells. Moreover, Cur-Cu@PEG displayed acceptable biocompatibility . Furthermore, Cur-Cu@PEG alleviated CP-AKI and RM-AKI in mice with kidney-targeted delivery. Mechanistically, Cur-Cu@PEG effectively lessened the production of ROS, thereby repressing caspase-3-dependent apoptotic/pyroptotic cell death in the kidneys of AKI mice. Altogether, these results offer a viable approach for synthesizing antioxidant metal phenolic networks mimics to ameliorate ROS-related diseases.