Sepsis is an aberrant systemic inflammatory response mediated by excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Developing an efficient antioxidant therapy for sepsis scavenging ROS and RNS remains a big challenge owing to the insufficient activity and sustainability of conventional antioxidants. Herein, biocompatible transition-metal dichalcogenide antioxidants with excellent scavenging activity and sustainability for HO, O, OH, and nitric oxide are developed for effective sepsis treatment. WS, MoSe, and WSe nanosheets exfoliated and functionalized with a biocompatible polymer effectively scavenge mitochondrial and intracellular ROS and RNS in inflammatory cells. Among the nanosheets, WS most efficiently suppresses the excessive secretion of inflammatory cytokines along with scavenging ROS and RNS without affecting the expression levels of the anti-inflammatory cytokine and ROS-producing enzymes. The WS nanosheets significantly improve the survival rate up to 90% for severely septic mice by reducing systemic inflammation. The pharmacokinetics suggests that the WS nanosheets can be excreted from mice 3 days after intravenous injection. This work demonstrates the potential of therapeutic nanosheet antioxidants for effective treatment of ROS and RNS-related diseases.