Acute kidney injury (AKI) has been a global public health concern leading to high patient morbidity and mortality in the world. Nanotechnology-mediated antioxidative therapy has facilitated the treatment of AKI. Herein, a hierarchical curcumin-loaded nanodrug delivery system (NPS@Cur) was fabricated for antioxidant therapy to ameliorate AKI. The nanoplatform could respond to subacidic and reactive oxygen species (ROS) microenvironments. The subacidic microenvironment led to a smaller size (from 140.9 to 99.36 nm) and positive charge (from -4.9 to 12.6 mV), contributing to the high accumulation of nanoparticles. An excessive ROS microenvironment led to nanoparticle degradation and drug release. In vitro assays showed that NPS@Cur could scavenge excessive ROS and relieve oxidative stress in HO-induced HK-2 cells through reduced apoptosis, activated autophagy, and decreased endoplasmic reticulum stress. Results from cisplatin-induced AKI models revealed that NPS@Cur could effectively alleviate mitochondria injury and protect kidneys via antioxidative protection, activated autophagy, decreased endoplasmic reticulum stress, and reduced apoptosis. NPS@Cur showed excellent biocompatibility and low toxicity to primary tissues in mice. These results revealed that NPS@Cur may be a potential therapeutic strategy for efficiently treating cisplatin or other cause-induced AKI.