Acute kidney injury (AKI) is a dynamic process associated with inflammation, oxidative stress, and lipid peroxidation, in which mitochondrial mitophagy and macrophage polarization play a critical role in the pathophysiology. Based on the expression of the CD44 receptor on renal tubular epithelial cells (RTECs) and activated M1 macrophages being abnormally increased, accompanied by up-regulation of reactive oxygen species (ROS) during AKI, the conjugates of bilirubin (BR), an endogenous antioxidant which has the property of anti-inflammation, and chondroitin sulfate (CS) with CD44-targeting property could be a promising therapeutic carrier. In this study, we develop a CD44-targeted/ROS-responsive CS-BR-mediated multifunctional liposome loading celastrol (CS-BR@CLT) for the targeted therapy of AKI. CS-BR@CLT is shown to selectively accumulate in AKI mouse kidneys via targeting of CD44 receptors. Treatment with CS-BR@CLT significantly ameliorates acute kidney injury caused by ischemia-reperfusion and protects renal function. Mechanistically, CS-BR@CLT inhibits apoptosis, protects mitochondria, promotes autophagy, regulates macrophage polarization, and alleviates interstitial inflammation. Overall, our study demonstrates that CS-BR@CLT could be a promising strategy to ameliorate acute kidney injury.