Acute kidney injury (AKI) is highly correlated with oxidative stress, and the application of antioxidants is one of the promising treatments. Salvianolic acid B (SAB) is a natural polyphenol with powerful antioxidant effects. Due to its inherent characteristic of inferior bioavailability, its clinical application is impeded. In this study, small SAB-incorporated nanoparticles (SFA) were synthesized via the self-assembly of SAB, ferric ions, and bovine serum albumin (BSA). Apart from antioxidant activity, the SFA nanoparticles were found to efficiently restore lysosome dysfunction induced by reactive oxygen species (ROS) in human kidney proximal tubular epithelial HK-2 cells. The small size and BSA incorporation make the SFA nanoparticles to be promising AKI-targeting nanoparticles. They are rapidly accumulated and long-term retained in injured kidneys of glycerol-induced AKI mice, especially in the proximal tubules which are the key lesion location during AKI. In vivo studies indicate that SFA nanoparticles show a superior protective effect compared with the free drug by suppressing oxidative stress and maintaining lysosome homeostasis indicated by enhanced heme oxygenase-1 (HO-1) expression and restored cathepsin B (CTSB) activity, respectively. In summary, this study develops a delivery system for the antioxidant SAB enhancing local delivery and offering an additional lysosome restoring mechanism for AKI therapy.