It is believed that oxidative stress is a key causing factor of liver damage induced by a variety of agents, and it is a major contributing factor in almost all conditions compromising liver function, including ischemia–reperfusion injury (IRI), nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, liver cirrhosis and hepatocellular carcinoma (HCC). Liver is the organ that high concentration of melatonin (N‐acetyl‐5‐methoxytryptamine) accumulates, and it is the sole organ where circulating melatonin is metabolized. Melatonin is one of the best antioxidants that protects liver, and its metabolites also have antioxidative function. Melatonin exerts its antioxidative function directly through its radical scavenging ability and indirectly through stimulation of antioxidant enzymes. The antioxidative response from melatonin in liver affects from various factors, including its dosage, route, time and duration of administration, the type of oxidative‐induced agent and species aging. This indoleamine is also an effective and promising antioxidative choice for targeting liver IRI, NAFLD, NASH, fibrosis, cirrhosis and HCC. This article is protected by copyright. All rights reserved