INTRODUCTION: Lung injury, a common complication of sepsis, arises from elevated reactive oxygen species (ROS), mitochondrial dysfunction, and cell death driven by inflammation. In this study, a novel class of ultrasmall nanoparticles (CuO USNPs) was developed to address sepsis-induced lung injury (SILI). METHODS: The synthesized nanoparticles were thoroughly characterized to assess their properties. In vitro experiments were conducted to determine the biologically effective concentration and elucidate the anti-inflammatory mechanism of action. These findings were further supported by in vivo studies, showcasing the material's efficacy in mitigating SILI. RESULTS: The CuO USNPs demonstrated remarkable scavenging capabilities for hydrogen peroxide (HO), superoxide anions (O ), and hydroxyl radicals (·OH), attributed to their catalase (CAT)- and superoxide dismutase (SOD)-like activities. Additionally, the nanoparticles exhibited strong anti-inflammatory effects, preserved mitochondrial homeostasis through potent ROS scavenging, and significantly reduced cell death. In vivo studies on mice further validated their protective role against SILI. THE CONCLUSION: This study highlights the therapeutic potential of CuO USNPs in treating sepsis-induced lung injury by effectively scavenging ROS and reducing cell death. These findings provide compelling evidence for the future use of copper-based nanoparticles as antioxidant therapeutics.