Acetaminophen (APAP) overdose is steadily becoming the chief reason for drug-induced acute liver failure, yet limited treatment is currently clinically available. Considering that the mechanism of APAP-induced hepatotoxicity is inseparable from oxidative stress and inflammation, a biocompatible Mn₃O₄ nanozyme mimicking superoxide dismutase (SOD) and catalase (CAT) activities and possessing reactive oxygen species (ROS)–scavenging capacity and antiapoptotic properties, is reported herein as a promising nanodrug to treat APAP-induced liver injury (AILI). Possessing bioactive enzyme–like functions, Mn₃O₄ nanoparticles (NPs) can not only reduce the oxidative stress on the liver by decreasing ROS accumulation but also downregulate the infiltration of inflammatory macrophages that secrete proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Notably, the bifunctional Mn₃O₄ NPs mediate nuclear factor–erythroid 2 p45-related factor 2 signaling pathway activation and nuclear factor kappa B signaling pathway inhibition to effectively prevent the already fragile APAP-overdosed murine hepatocytes from being attacked again, thus mitigating hepatocyte apoptosis and alleviating APAP-induced liver damage. Thus, the Mn₃O₄ nanozyme (Mn₃O₄ NPs) evaluated in this study has potential preventive and therapeutic effects on AILI.