This study focuses on the treatment of cisplatin-induced acute kidney injury (AKI). Extensive research has demonstrated that oxidative stress and inflammatory responses caused by excessive production of reactive oxygen species (ROS) play a critical role in the progression of AKI. Therefore, exploring effective and safe antioxidants and anti-inflammatory agents to scavenge overexpressed ROS and regulate excessive inflammation has become a promising therapeutic strategy. Glutathione and iron selenide both possess anti-inflammatory and antioxidant properties. Based on this, we successfully developed glutathione-modified iron selenide nanoparticles (GSH-Fe_3-XSe₃ NPs) with a particle size of approximately 200 nm, which exhibit excellent biosafety. This study comprehensively investigated the antioxidant and anti-inflammatory capabilities of GSH-Fe_3-XSe₃ NPs. Firstly, the anti-inflammatory and antioxidant properties of GSH-Fe_3-XSe₃ NPs were assessed at the cellular level. Additionally, the effects of GSH-Fe_3-XSe₃ NPs on ROS and MDA levels and the expression of inflammation-related cytokines (TNF-α, IL-6) in lipopolysaccharide (LPS)-induced inflammatory cells were investigated. The antagonistic effect of GSH-Fe_3-XSe₃ NPs on LPS-induced inflammation in RAW264.7 cells was confirmed. Secondly, the anti-inflammatory mechanism of GSH-Fe_3-XSe₃ NPs was explored using WB. Finally,in this study, an AKI mouse model was established by intraperitoneal injection of cisplatin. The safe dosage of GSH-Fe_3-XSe₃ NPs in healthy mice was determined, and the biosafety of GSH-Fe_3-XSe₃ NPs was analyzed. The therapeutic effect of GSH-Fe_3-XSe₃ NPs on mice with acute kidney injury was evaluated by measuring serum levels of AKI-related inflammatory factors. Experimental results demonstrated that GSH-Fe_3-XSe₃ NPs can simultaneously scavenge ROS, malondialdehyde (MDA), and nitric oxide (NO), showing excellent cytoprotective effects against oxidative stress-mediated damage. Furthermore, in a cisplatin-induced AKI mouse model, GSH-Fe_3-XSe₃ NPs significantly reduced the expression levels of blood urea nitrogen (BUN), serum creatinine (SCR), MDA, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) under AKI conditions, markedly improving the symptoms of AKI mice. In conclusion, the GSH-Fe_3-XSe₃ NPs prepared in this study, through their dual mechanisms of antioxidant and anti-inflammatory actions, achieved therapy for cisplatin-induced AKI, providing a novel therapeutic approach for AKI treatment.