Lipid accumulation is a factor contributing to the pathogenesis of acute kidney injury (AKI), yet there are currently no approved pharmacotherapies aside from adjuvant therapy. A developed reactive oxygen species (ROS)-responsive drug delivery system (NPS@Cur) was developed to deliver the autophagy activator curcumin (Cur) in order to alleviate AKI by activating autophagy and promoting lipid droplet degradation. The nanoparticles were shown to be ROS-responsive in the HO medium and demonstrate ROS-responsive uptake in palmitate (PA)-induced oxidative stress-damaged cells. NPS@Cur was found to effectively inhibit lipid accumulation by autophagosome transport in kidney tubular cells. Additionally, in a mouse AKI model, NPS@Cur was observed to significantly ameliorate renal damage by activating autophagy flux and improving lipid transport. These results suggest that the ROS-responsive drug delivery system augmented the therapeutic effect of Cur on AKI by improving lipid metabolism through autophagy activation. Therefore, targeting lipid metabolism with NPS@Cur may be a promising AKI treatment strategy.