Carbon monoxide (CO) is an important effector-signaling molecule involved in various pathophysiological processes. Here we investigated the protective effects of exogenous CO in a murine model of acute liver damage induced by d-galactosamine (GalN) and lipopolysaccharide (LPS). Exogenous CO gas was administered to mice via intraperitoneal injection (first at a dose of 15 ml kg−1 and then, 6 h later, 8 ml kg−1), which caused a significant elevation of blood carboxyhemoglobin levels of up to 12–14% for more than 12 h. GalN/LPS were given to induce acute liver damage in mice 30 min prior to CO exposure. This showed that GalN/LPS induced severe liver injury in mice, whereas CO injection remarkably improved the survival rate of mice and led to attenuated hepatocellular damage. CO exhibited anti-oxidative capabilities by inhibiting hepatic malondialdehyde contents and restoring superoxide dismutase and glutathione, as well as by reducing inducible NOS/NO production. The anti-apoptotic and anti-inflammatory effects of CO were substantial, characterized by a notable inhibition of hepatocyte apoptosis and a reduction of pro-inflammatory cytokines in mice. Our findings thus supported the hypothesis that exogenous CO provides protective effects against acute liver damage in mice, mainly dependent on its anti-oxidative, anti-inflammatory and anti-apoptotic properties. Copyright © 2012 John Wiley & Sons, Ltd.