Acute kidney injury (AKI) is a critical condition marked by a rapid decline in renal function, primarily driven by oxidative stress, mitochondrial dysfunction, and inflammation. Despite extensive research, effective therapeutic strategies addressing the complex pathophysiology of AKI remain limited. In this study, we prepared a tannic acid‑cerium nanoenzyme (TA-Ce) and explored its potential for treating AKI. TA-Ce, synthesized via a one-pot method, demonstrated strong reactive oxygen species (ROS) scavenging, therapeutic efficacy, and biocompatibility in vitro and in vivo. TA-Ce, approximately 25.6 nm in size, was obtained by optimizing the molar ratios of TA to Ce and pH conditions, resulting in effective accumulation in the injured kidney. In addition, TA-Ce exhibited broad-spectrum antioxidant ability, capable of scavenging various ROS and alleviating oxidative stress. Notably, TA-Ce outperformed the conventional anti-inflammatory drug N-acetylcysteine (NAC) in both rhabdomyolysis-induced AKI (RM-AKI) and cisplatin-induced AKI (CP-AKI) mouse models. Mechanistic studies in RM-AKI revealed that TA-Ce disrupted the vicious cycle of oxidative stress, mitochondrial damage, endoplasmic reticulum stress, apoptosis, and inflammation. The nanoenzyme restored mitochondrial autophagic flux by inhibiting the P62-LC3 signaling pathway and alleviated endoplasmic reticulum stress by suppressing the IRE1-XBP1s pathway. Consequently, this prevented the downstream activation of the Bcl-2-Bax-Cyt-c-Cleaved Casp-3 apoptotic pathway and the NF-κB inflammatory pathway, ultimately ameliorating RM-AKI. This study lays a strong foundation for the development of metal-polyphenol nanomaterials as a therapeutic strategy for clinical AKI.