Background & Aims: Reactive oxygen species (ROS) are considered to play a prominent causative role in the development of various hepatic disorders. Antioxidants have been effectively demonstrated to protect against hepatic damage. Hydrogen (H ₂), a new antioxidant, was reported to selectively reduce the strongest oxidants, such as hydroxyl radicals (OH) and peroxynitrite (ONOO ^-), without disturbing metabolic oxidation-reduction reactions or disrupting ROS involved in cell signaling. In place of H ₂ gas, hydrogen-rich saline (HS) may be more suitable for clinical application. We herein aim to verify its protective effects in experimental models of liver injury. Methods: H ₂ concentration in vivo was detected by hydrogen microelectrode for the first time. Liver damage, ROS accumulation, cytokine levels, and apoptotic protein expression were, respectively, evaluated after GalN/LPS, CCl ₄, and DEN challenge. Simultaneously, CCl ₄-induced hepatic cirrhosis and DEN-induced hepatocyte proliferation were measured. Results: HS significantly increased hydrogen concentration in liver and kidney tissues. As a result, acute liver injury, hepatic cirrhosis, and hepatocyte proliferation were reduced through the quenching of detrimental ROS. Activity of pro-apoptotic players, such as JNK and caspase-3, were also inhibited. Conclusions: HS could protect against liver injury and also inhibit the processes leading to liver cirrhosis and hepatocyte compensatory proliferation.